{"gene":"CLEC5A","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1999,"finding":"CLEC5A (MDL-1) is a type II transmembrane C-type lectin that associates non-covalently with DAP12 via a charged residue in its transmembrane region; crosslinking of MDL-1/DAP12 complexes on macrophages results in calcium mobilization, establishing a myeloid cell activation pathway.","method":"Molecular cloning, co-association assay, calcium mobilization assay in J774 macrophage cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — original molecular cloning plus functional readout (calcium mobilization), independently replicated by subsequent studies confirming DAP12 association","pmids":["10449773"],"is_preprint":false},{"year":2008,"finding":"CLEC5A directly interacts with dengue virions (without viral entry) and triggers DAP12 phosphorylation, stimulating proinflammatory cytokine release from macrophages; blockade of CLEC5A suppresses cytokine secretion and reduces DV-induced plasma leakage and mortality in STAT1-deficient mice without affecting IFN-α release.","method":"Direct binding assay (CLEC5A–dengue virion interaction), DAP12 phosphorylation assay, anti-CLEC5A monoclonal antibody blockade, in vivo STAT1-deficient mouse model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (direct binding, phosphorylation assay, antibody blockade, in vivo model) in a single rigorous study, widely replicated","pmids":["18496526"],"is_preprint":false},{"year":2009,"finding":"MDL-1 (CLEC5A) associates with both DAP12 and DAP10 in osteoclasts and bone marrow-derived macrophages, forming trimolecular MDL-1–DAP12/DAP10 complexes; DAP10 association depends almost entirely on DAP12. MDL-1-mediated stimulation augments osteoclastogenesis in vitro, and DAP10-deficient mice become osteopetrotic with reduced osteoclasts.","method":"Co-immunoprecipitation, in vitro osteoclastogenesis assay, DAP10-knockout mouse phenotype analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP demonstrating trimolecular complex plus KO mouse phenotype with defined cellular readout, multiple orthogonal methods","pmids":["19251634"],"is_preprint":false},{"year":2010,"finding":"MDL-1 (CLEC5A) activation enhances recruitment of inflammatory macrophages and neutrophils to joints and promotes bone erosion in autoimmune arthritis; genetic deletion of Mdl1 or treatment with MDL-1-Ig fusion protein reduces clinical signs of joint inflammation.","method":"Mdl1 gene deletion (knockout mice), MDL-1-Ig fusion protein treatment, autoimmune arthritis model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus therapeutic blockade with defined cellular and pathological phenotype readouts","pmids":["20212065"],"is_preprint":false},{"year":2010,"finding":"CLEC5A expression in monocytes/macrophages and granulocytes is transcriptionally regulated by the myeloid transcription factor PU.1, which binds directly to the CLEC5A promoter in vivo.","method":"Microarray profiling, PU.1 knockdown/restoration, CLEC5A promoter reporter assay, chromatin immunoprecipitation (ChIP) for PU.1 binding","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — promoter reporter assay plus in vivo ChIP demonstrating direct PU.1 binding, single lab but multiple orthogonal methods","pmids":["21094529"],"is_preprint":false},{"year":2011,"finding":"CLEC5A is homodimeric at the cell surface. A crystal structure (1.9 Å) revealed a β-sheet extension acting as a binary switch regulating molecular flexibility; extracellular conformational changes may be transmitted through the membrane to influence DAP12 signaling. CLEC5A binds dengue virus serotypes 1–4.","method":"X-ray crystallography (1.9 Å), molecular dynamics simulations, glycan microarray, docking studies, cell-surface binding experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by multiple complementary methods (MD simulation, glycan array, docking, binding assays) in single rigorous study","pmids":["21566123"],"is_preprint":false},{"year":2011,"finding":"Activation of MDL-1 (CLEC5A) on immature CD11b+Gr-1+Ly6G+Ly6C+ myeloid cells triggers NO and TNF-α production via a DAP12/DAP10/Syk/PI3K/Akt/eNOS (not iNOS) signaling cascade, leading to shock; Akt physically interacts with and activates eNOS in this pathway.","method":"In vivo ConA liver injury model, MDL-1 agonist antibody treatment, MDL-1+ cell depletion, genetic knockouts, co-immunoprecipitation (Akt–eNOS interaction), pharmacological inhibition of Syk/PI3K/Akt","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP plus KO/depletion plus pharmacological pathway dissection, multiple orthogonal methods in one study","pmids":["22005300"],"is_preprint":false},{"year":2012,"finding":"CLEC5A is required for dengue virus-induced NLRP3 inflammasome activation and caspase-1-dependent IL-1β/IL-18 secretion and pyroptosis in GM-CSF-polarized (inflammatory) macrophages; blockade of CLEC5A inhibits NLRP3 inflammasome activation and pyroptosis.","method":"Anti-CLEC5A antibody blockade, caspase-1 activation assay, IL-1β/IL-18 ELISA, pyroptosis readout in GM-Mφ vs M-Mφ","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — antibody blockade with multiple downstream readouts (caspase-1, cytokines, cell death) in defined macrophage subsets, single lab but multiple orthogonal assays","pmids":["23152543"],"is_preprint":false},{"year":2016,"finding":"CLEC5A interacts with the hemagglutinin protein of influenza viruses; CLEC5A-mediated signaling enhances proinflammatory cytokine (TNF-α, IP-10) production in macrophages without affecting viral replication; CLEC5A-deficient macrophages show elevated IFN-α and upregulated TLR3 after dsRNA treatment; CLEC5A-deficient mice show reduced lung inflammation and improved survival after lethal H5N1 challenge.","method":"Lectin screening identifying HA–CLEC5A interaction, siRNA silencing, anti-CLEC5A antibody blockade, Syk inhibitor, CLEC5A-KO mouse infection model","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (lectin screen, KD, antibody blockade, KO mice) identifying HA interaction and downstream signaling, single lab","pmids":["27795434"],"is_preprint":false},{"year":2016,"finding":"Dengue virus infection activates Nrf2 via PERK-mediated ER stress, which drives transcriptional upregulation of CLEC5A; elevated CLEC5A then enhances TLR3-independent TNF-α production; the DENV NS2B3 protein is sufficient to induce Nrf2 nuclear translocation and CLEC5A expression.","method":"Nrf2 nuclear translocation assay, PERK inhibition, CLEC5A promoter activation, NS2B3 forced expression, TNF-α ELISA, in vivo mouse brain analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (nuclear translocation, inhibitor, forced expression, in vivo) but single lab","pmids":["27561946"],"is_preprint":false},{"year":2016,"finding":"Dengue virus–CLEC5A interaction forms a multivalent hetero-complex with the mannose receptor (MR)/DC-SIGN on macrophages: MR/DC-SIGN first captures virus with high avidity, enabling low-avidity CLEC5A to engage virus in close proximity and initiate signaling.","method":"Co-immunoprecipitation, proximity-based binding assays, blocking experiments with anti-MR/DC-SIGN antibodies","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown/co-IP evidence for hetero-complex formation, single lab, mechanistic model partly inferred from binding data","pmids":["27832191"],"is_preprint":false},{"year":2017,"finding":"CLEC5A is required for neutrophil extracellular trap (NET) formation, ROS production, and proinflammatory cytokine (IL-1β, IL-17A, TNF) release in response to Listeria monocytogenes; Clec5a-/- mice show rapid bacterial dissemination, severe liver necrosis, and increased mortality, and CLEC5A engages bacterial peptidoglycan (GlcNAc/MurNAc disaccharides).","method":"Clec5a-/- mouse infection model, NET formation assay, ROS measurement, cytokine ELISA, liver histopathology, flow cytometry","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with multiple defined cellular phenotypes, bacterial load quantification, and histopathology; multiple orthogonal readouts","pmids":["28824166"],"is_preprint":false},{"year":2019,"finding":"Dengue virus activates platelets via CLEC2 to release extracellular vesicles (exosomes and microvesicles); these EVs activate CLEC5A and TLR2 on neutrophils and macrophages, inducing NET formation and proinflammatory cytokine release; simultaneous blockade of CLEC5A and TLR2 increases survival from 30% to 90% in dengue-infected stat1-/- mice.","method":"EV isolation and characterization, anti-CLEC5A/anti-TLR2 antibody blockade, NET formation assay, clec5a-/-/tlr2-/- double-KO mouse model, survival analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — EV functional assay, double-KO mouse model, antibody blockade with defined phenotypic readouts, multiple orthogonal methods in one study","pmids":["31160588"],"is_preprint":false},{"year":2022,"finding":"SARS-CoV-2-activated platelets produce extracellular vesicles that induce NET formation via CLEC5A and TLR2 on neutrophils; simultaneous genetic ablation of CLEC5A and TLR2 (clec5a-/-/tlr2-/- mice) dramatically attenuates SARS-CoV-2-induced lung thromboinflammation in vivo.","method":"EV isolation from COVID-19 patient sera, anti-CLEC5A/anti-TLR2 antibody blockade, clec5a-/-/tlr2-/- double-KO mouse model, NET formation assay, in vivo lung inflammation assessment","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — double-KO mouse model plus antibody blockade plus in vitro EV assays, multiple orthogonal methods, single lab","pmids":["35820906"],"is_preprint":false},{"year":2023,"finding":"CLEC5A mediates Zika virus-induced testicular inflammation; in clec5a-/-/stat1-/- mice, ZIKV-induced testicular inflammation, neutrophil infiltration, and sperm damage are reduced; CLEC5A-associated DAP12 signaling regulates ZIKV-induced testicular damage, as dap12-/-/stat1-/- mice phenocopy clec5a-/- mice.","method":"Clec5a-/- and dap12-/- KO mouse ZIKV infection model, immunohistochemistry, qRT-PCR for viral titer, cytokine measurement, spermatozoa counting/motility","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two independent KO mouse lines (CLEC5A and DAP12) with convergent phenotypes, multiple orthogonal readouts, single lab","pmids":["36803804"],"is_preprint":false},{"year":2022,"finding":"IL-23 induces expansion of a myeloid MDL-1+CD11b+Ly6G+ osteoclast precursor population; genetic ablation of MDL-1 (CLEC5A) completely prevents IL-23-induced osteoclastogenesis and bone destruction in inflammatory arthritis; MDL-1-/- mice have increased bone mineral density.","method":"In vivo IL-23 gene transfer, spectral flow cytometry, micro-CT bone analysis, Western blotting, immunoprecipitation, MDL-1-KO mouse osteoclastogenesis assay","journal":"Arthritis & rheumatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse model plus in vivo gene transfer plus multiple bone phenotype readouts, multiple orthogonal methods, single lab","pmids":["36787107"],"is_preprint":false},{"year":2022,"finding":"MDL-1 (CLEC5A) on osteoclast precursors is upregulated during intestinal inflammation; anti-MDL-1 antibody treatment abrogates enhanced osteoclast differentiation ex vivo and ameliorates bone loss during colitis in vivo.","method":"Multiple murine colitis models, anti-MDL-1 antibody treatment, ex vivo osteoclast differentiation assay, flow cytometry, micro-CT","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — therapeutic antibody blockade plus ex vivo functional assay plus multiple in vivo models with defined skeletal phenotype","pmids":["35835390"],"is_preprint":false},{"year":2025,"finding":"Endothelial CLEC5A drives vascular barrier dysfunction in sepsis; endothelial-specific knockdown of CLEC5A improves survival and reduces vascular leakage in CLP-challenged mice; in vitro, CLEC5A deletion maintains trans-endothelial electrical resistance and inhibits monocyte/neutrophil adhesion and trans-endothelial migration under LPS stimulation.","method":"Endothelial-specific CLEC5A knockdown, CLEC5A re-expression rescue, CLP sepsis mouse model, single-cell RNA sequencing, trans-endothelial electrical resistance assay, monocyte/neutrophil adhesion and migration assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KD with rescue experiment plus in vitro barrier assays plus in vivo survival model, multiple orthogonal methods","pmids":["40498836"],"is_preprint":false},{"year":2021,"finding":"CLEC5A knockdown in a myocardial infarction model suppresses macrophage M1 polarization, NLRP3 inflammasome activation, pyroptosis, and NF-κB signaling in the left ventricle; in vitro, CLEC5A knockdown inhibits LPS/IFNγ-stimulated M1 polarization in RAW264.7 cells and blocks polarized macrophage-induced NLRP3/pyroptosis in co-cultured cardiomyocytes.","method":"In vivo adenoviral shRNA knockdown, mouse MI model, in vitro co-culture, Western blot for NLRP3/caspase-1/NF-κB, macrophage polarization assay","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with multiple downstream readouts but single lab, no KO rescue experiment","pmids":["33939927"],"is_preprint":false},{"year":2024,"finding":"Clec5a knockout microglia show enhanced phagocytosis of Aβ; in AD mice, Clec5a knockout reduces Aβ deposition, increases microglia coverage around plaques, and ameliorates memory deficits; CLEC5A normally restrains microglial Aβ clearance.","method":"Clec5a-/- × AD mouse model crosses, Morris water maze, ELISA for Aβ, immunohistochemistry, fluorescent-labeled Aβ phagocytosis assay in knockdown microglial lines and KO primary microglia","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model plus in vitro phagocytosis assay, multiple readouts, single lab","pmids":["39443966"],"is_preprint":false},{"year":2024,"finding":"CLEC5A interacts with TREM1; this interaction mediates NLRC4 expression and thereby promotes neuronal pyroptosis in a spinal cord injury model; knockdown of CLEC5A, TREM1, or NLRC4 attenuates pyroptosis markers (LDH, GSDMD-N, caspase-1, IL-1β, IL-18).","method":"Co-immunoprecipitation (CLEC5A–TREM1 interaction), siRNA knockdown in PC12 cells and in vivo rat SCI model, Western blot for pyroptosis markers","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single co-IP identifying CLEC5A–TREM1 interaction, knockdown phenotype supports functional link, single lab","pmids":["39187376"],"is_preprint":false},{"year":2025,"finding":"CLEC5A epigenetic upregulation via DNMT1-mediated demethylation of CpG site cg06744540 drives CLEC5A overexpression in monocytes/macrophages; elevated CLEC5A activates NF-κB signaling to enhance inflammation, migration, adhesion, macrophage polarization, lipid accumulation, and inhibit apoptosis; folic acid increases DNMT1 expression, reduces CLEC5A, and suppresses atherosclerotic plaque formation in vivo.","method":"Methylome–transcriptome integration, DNMT1 overexpression, CpG site mapping, NF-κB pathway analysis, functional assays (migration, adhesion, lipid accumulation), high-fat ApoE-/- mouse model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic mapping plus functional rescue with DNMT1/folic acid plus in vivo model, multiple orthogonal methods, single lab","pmids":["40147659"],"is_preprint":false},{"year":2024,"finding":"In tolerogenic dendritic cells (tolDCs), Clec5a promotes IL-10 production and Foxp3+ Treg induction while suppressing NF-κB signaling and IL-6; Clec5a-knockdown tolDCs show reduced immunomodulatory function; administration of Clec5a-expressing DCs ameliorates dopaminergic neuron loss, reduces α-synuclein accumulation, and improves locomotor behavior in MPTP-induced PD mice.","method":"Clec5a knockdown in tolDCs, cytokine ELISA (IL-10, IL-6), Foxp3+ Treg quantification, NF-κB signaling assay, MPTP mouse model, immunohistochemistry","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD in tolDCs with defined cytokine readouts plus in vivo rescue, single lab, single study","pmids":["40917058"],"is_preprint":false},{"year":2019,"finding":"CLEC5A binds fucose and mannose moieties of dengue virus membrane glycans, as well as GlcNAc/MurNAc disaccharides of bacterial cell walls, establishing its dual ligand-recognition properties as a pattern recognition receptor.","method":"Glycan binding assays, structural analyses reviewed in the context of prior crystallography and binding studies","journal":"Advances in experimental medicine and biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review synthesizing multiple prior experimental binding studies; carbohydrate specificity established by prior glycan array (PMID 21566123) and bacterial studies (PMID 28824166)","pmids":["32152943"],"is_preprint":false},{"year":2059,"finding":"REEP5 physically binds CLEC5A and its overexpression abolishes CLEC5A-induced ER stress-mediated apoptosis in cardiomyocytes, placing REEP5 as a negative regulator of CLEC5A-driven cardiac cell death.","method":"Co-immunoprecipitation (REEP5–CLEC5A interaction), REEP5 overexpression in hypoxia-induced cardiomyocyte model, ER stress markers (PERK, IRE1α, ATF6, CHOP, caspase-12), in vivo MI mouse model","journal":"BMC cardiovascular disorders","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP interaction claim, single lab, mechanistic context derived from overexpression without KO validation","pmids":["39044150"],"is_preprint":false}],"current_model":"CLEC5A (MDL-1/CLECSF5) is a type II transmembrane C-type lectin on myeloid cells (monocytes, macrophages, neutrophils, dendritic cells) and endothelial cells that signals through a non-covalent association with the ITAM-bearing adaptor DAP12 (and cooperatively with DAP10), activating a Syk/PI3K/Akt cascade; it acts as a pattern recognition receptor for flavivirus glycans (via terminal fucose/mannose), bacterial peptidoglycan (GlcNAc/MurNAc), and platelet-derived extracellular vesicles (via TLR2 co-engagement), driving proinflammatory cytokine production, NLRP3 inflammasome activation, NET formation, osteoclastogenesis, and vascular barrier dysfunction, while its transcription is controlled by PU.1 and by Nrf2 during viral infection."},"narrative":{"mechanistic_narrative":"CLEC5A (MDL-1/CLECSF5) is a type II transmembrane C-type lectin on myeloid and endothelial cells that functions as a pattern-recognition receptor coupling pathogen and damage signals to proinflammatory myeloid activation [PMID:10449773, PMID:18496526]. It lacks an intrinsic signaling motif and instead transduces signals through non-covalent association with the ITAM-bearing adaptor DAP12 via a charged transmembrane residue, with cooperative recruitment of DAP10, triggering calcium mobilization and a Syk/PI3K/Akt cascade that in immature myeloid cells drives NO and TNF-α production through Akt-activated eNOS [PMID:10449773, PMID:19251634, PMID:22005300]. As a receptor, homodimeric CLEC5A recognizes terminal fucose/mannose glycans on flavivirus virions, influenza hemagglutinin, and GlcNAc/MurNAc disaccharides of bacterial peptidoglycan, and engages platelet-derived extracellular vesicles in concert with TLR2 [PMID:21566123, PMID:27795434, PMID:28824166, PMID:31160588, PMID:32152943]. Through these ligands CLEC5A drives proinflammatory cytokine release, NLRP3 inflammasome activation and pyroptosis, neutrophil extracellular trap formation, and vascular barrier dysfunction across dengue, Zika, influenza, SARS-CoV-2, bacterial, and sepsis models, where its genetic or antibody-mediated blockade reduces inflammation and improves survival [PMID:18496526, PMID:23152543, PMID:28824166, PMID:31160588, PMID:35820906, PMID:40498836]. CLEC5A additionally promotes osteoclastogenesis and inflammatory bone erosion in arthritis and colitis, and its transcription is controlled by the myeloid factor PU.1 and induced by Nrf2 during viral infection [PMID:19251634, PMID:20212065, PMID:36787107, PMID:35835390, PMID:21094529, PMID:27561946].","teleology":[{"year":1999,"claim":"Established CLEC5A as a myeloid activating receptor by showing it has no intrinsic signaling capacity but couples to the ITAM adaptor DAP12 to mobilize calcium, defining the core signaling logic.","evidence":"Molecular cloning, co-association assay and calcium mobilization in J774 macrophages","pmids":["10449773"],"confidence":"High","gaps":["Endogenous ligand unknown at this stage","Downstream effector cascade beyond calcium not defined"]},{"year":2008,"claim":"Identified the first physiological context for CLEC5A as a flavivirus sensor, showing direct dengue virion binding triggers DAP12 phosphorylation and pathogenic cytokine release driving plasma leakage in vivo.","evidence":"Direct binding assay, DAP12 phosphorylation, anti-CLEC5A blockade and STAT1-deficient mouse model","pmids":["18496526"],"confidence":"High","gaps":["Precise glycan ligand on virion not yet resolved","Cofactor requirements for low-avidity engagement unaddressed"]},{"year":2009,"claim":"Expanded the receptor complex to a trimolecular MDL-1–DAP12/DAP10 assembly and linked CLEC5A signaling to osteoclastogenesis, broadening its role beyond infection to bone homeostasis.","evidence":"Co-immunoprecipitation, in vitro osteoclastogenesis and DAP10-knockout mouse phenotyping","pmids":["19251634"],"confidence":"High","gaps":["Ligand driving osteoclast-context activation unclear","Relative signaling contributions of DAP12 vs DAP10 not dissected"]},{"year":2010,"claim":"Demonstrated CLEC5A as a pathogenic driver of inflammatory arthritis and defined its transcriptional control by PU.1, connecting receptor expression to myeloid lineage programming.","evidence":"Mdl1 knockout and MDL-1-Ig blockade in arthritis model; ChIP and promoter reporter for PU.1 binding","pmids":["20212065","21094529"],"confidence":"High","gaps":["Endogenous arthritis-relevant ligand not identified","Additional transcriptional regulators not explored"]},{"year":2011,"claim":"Provided structural and mechanistic detail by solving the crystal structure revealing a homodimer with a conformational binary switch, and dissected the DAP12/DAP10/Syk/PI3K/Akt/eNOS cascade leading to shock.","evidence":"X-ray crystallography with MD/glycan array/docking; in vivo ConA liver injury with co-IP and pharmacological pathway dissection","pmids":["21566123","22005300"],"confidence":"High","gaps":["How extracellular conformational change is transmitted to DAP12 not directly demonstrated","eNOS-vs-iNOS branching context dependence incompletely mapped"]},{"year":2012,"claim":"Linked CLEC5A to inflammasome biology by showing it is required for dengue-induced NLRP3 activation, caspase-1-dependent IL-1β/IL-18 release and pyroptosis selectively in inflammatory macrophages.","evidence":"Anti-CLEC5A blockade, caspase-1 and cytokine assays in GM-CSF vs M-CSF macrophages","pmids":["23152543"],"confidence":"High","gaps":["Molecular link between CLEC5A signaling and NLRP3 assembly not resolved","Reason for macrophage-subset specificity unexplained"]},{"year":2016,"claim":"Broadened ligand recognition to influenza hemagglutinin and defined how viral infection feeds back to upregulate CLEC5A via PERK/Nrf2 ER stress, and how virus engages CLEC5A cooperatively with MR/DC-SIGN.","evidence":"Lectin screen, siRNA/blockade and CLEC5A-KO H5N1 infection; Nrf2 translocation and NS2B3 forced expression; co-IP and proximity binding with MR/DC-SIGN","pmids":["27795434","27561946","27832191"],"confidence":"Medium","gaps":["MR/DC-SIGN hetero-complex model partly inferred from binding data","Nrf2 axis from single lab"]},{"year":2017,"claim":"Established CLEC5A as a bacterial sensor recognizing peptidoglycan GlcNAc/MurNAc and required for NET formation and antibacterial defense, generalizing its pattern-recognition role beyond viruses.","evidence":"Clec5a-/- Listeria infection model with NET, ROS, cytokine and histopathology readouts","pmids":["28824166"],"confidence":"High","gaps":["Structural basis of disaccharide recognition not solved","Contribution to other bacterial infections untested"]},{"year":2019,"claim":"Defined a platelet–EV–CLEC5A/TLR2 axis whereby virus-activated platelets release vesicles that co-engage CLEC5A and TLR2 to drive NETosis, and consolidated dual carbohydrate ligand specificity.","evidence":"EV functional assays, dual antibody blockade and clec5a-/-/tlr2-/- double-KO dengue mouse survival; review of glycan specificity","pmids":["31160588","32152943"],"confidence":"High","gaps":["EV cargo recognized by CLEC5A not identified","Mechanism of CLEC5A–TLR2 cooperation undefined"]},{"year":2022,"claim":"Extended the EV/CLEC5A/TLR2 NETosis axis to SARS-CoV-2 thromboinflammation and demonstrated CLEC5A as the essential driver of IL-23-induced and colitis-associated osteoclastogenesis and bone destruction.","evidence":"clec5a-/-/tlr2-/- COVID lung inflammation model; IL-23 gene transfer with micro-CT and MDL-1-KO; colitis models with anti-MDL-1 antibody","pmids":["35820906","36787107","35835390"],"confidence":"High","gaps":["Whether the same EV ligands operate across diseases unconfirmed","Direct osteoclast-precursor activating ligand unidentified"]},{"year":2023,"claim":"Confirmed DAP12 as the obligate signaling partner for CLEC5A-driven tissue pathology in vivo by showing dap12-/- mice phenocopy clec5a-/- mice in Zika-induced testicular inflammation.","evidence":"Clec5a-/- and dap12-/- ZIKV infection models with histology, viral titer and sperm function readouts","pmids":["36803804"],"confidence":"High","gaps":["Glycan ligand on ZIKV not specified","Cell type initiating testicular damage not isolated"]},{"year":2025,"claim":"Identified an endothelial role for CLEC5A in vascular barrier dysfunction and an epigenetic mechanism (DNMT1/CpG demethylation) driving monocyte CLEC5A overexpression and NF-κB-dependent atherogenic inflammation.","evidence":"Endothelial-specific knockdown with rescue in CLP sepsis plus barrier/adhesion assays; methylome–transcriptome integration with DNMT1/folic acid in ApoE-/- model","pmids":["40498836","40147659"],"confidence":"High","gaps":["Endothelial CLEC5A ligand and DAP12 dependence in endothelium not defined","Atherosclerosis epigenetic axis from single lab"]},{"year":2024,"claim":"Revealed context-dependent and tissue-protective or regulatory roles for CLEC5A, including restraint of microglial Aβ clearance, a TREM1–NLRC4 pyroptosis axis, and tolerogenic DC immunomodulation.","evidence":"Clec5a-/- AD crosses with phagocytosis assays; CLEC5A–TREM1 co-IP and knockdown in SCI; Clec5a knockdown tolDCs in PD model","pmids":["39443966","39187376","40917058"],"confidence":"Medium","gaps":["CLEC5A–TREM1 interaction rests on single co-IP without reciprocal validation","Mechanism of Aβ clearance restraint not defined","tolDC immunomodulation from single study"]},{"year":null,"claim":"How extracellular ligand binding and the homodimer conformational switch are mechanistically transmitted across the membrane to control DAP12/DAP10 ITAM signaling, and whether distinct ligands evoke distinct downstream programs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of a CLEC5A–DAP12 signaling complex","Ligand-specific signaling outcomes not directly compared","Determinants of pro- vs anti-inflammatory outcomes in different tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1,5,8]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[1,11,12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,23]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,7,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,18,20]}],"complexes":["CLEC5A–DAP12 complex","CLEC5A–DAP12–DAP10 trimolecular complex"],"partners":["DAP12","DAP10","TLR2","TREM1","REEP5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NY25","full_name":"C-type lectin domain family 5 member A","aliases":["C-type lectin superfamily member 5","Myeloid DAP12-associating lectin 1","MDL-1"],"length_aa":188,"mass_kda":21.5,"function":"Functions as a positive regulator of osteoclastogenesis (By similarity). Cell surface receptor that signals via TYROBP (PubMed:10449773). Regulates inflammatory responses (By similarity) (Microbial infection) Critical macrophage receptor for dengue virus serotypes 1-4 (PubMed:18496526, PubMed:21566123). The binding of dengue virus to CLEC5A triggers signaling through the phosphorylation of TYROBP (PubMed:18496526). This interaction does not result in viral entry, but stimulates pro-inflammatory cytokine release (PubMed:18496526)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NY25/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLEC5A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CLEC5A","total_profiled":1310},"omim":[{"mim_id":"614371","title":"DENGUE VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/614371"},{"mim_id":"604987","title":"C-TYPE LECTIN DOMAIN FAMILY 5, MEMBER A; CLEC5A","url":"https://www.omim.org/entry/604987"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone 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cloning, co-association assay, calcium mobilization assay in J774 macrophage cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — original molecular cloning plus functional readout (calcium mobilization), independently replicated by subsequent studies confirming DAP12 association\",\n      \"pmids\": [\"10449773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CLEC5A directly interacts with dengue virions (without viral entry) and triggers DAP12 phosphorylation, stimulating proinflammatory cytokine release from macrophages; blockade of CLEC5A suppresses cytokine secretion and reduces DV-induced plasma leakage and mortality in STAT1-deficient mice without affecting IFN-α release.\",\n      \"method\": \"Direct binding assay (CLEC5A–dengue virion interaction), DAP12 phosphorylation assay, anti-CLEC5A monoclonal antibody blockade, in vivo STAT1-deficient mouse model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (direct binding, phosphorylation assay, antibody blockade, in vivo model) in a single rigorous study, widely replicated\",\n      \"pmids\": [\"18496526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MDL-1 (CLEC5A) associates with both DAP12 and DAP10 in osteoclasts and bone marrow-derived macrophages, forming trimolecular MDL-1–DAP12/DAP10 complexes; DAP10 association depends almost entirely on DAP12. MDL-1-mediated stimulation augments osteoclastogenesis in vitro, and DAP10-deficient mice become osteopetrotic with reduced osteoclasts.\",\n      \"method\": \"Co-immunoprecipitation, in vitro osteoclastogenesis assay, DAP10-knockout mouse phenotype analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP demonstrating trimolecular complex plus KO mouse phenotype with defined cellular readout, multiple orthogonal methods\",\n      \"pmids\": [\"19251634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MDL-1 (CLEC5A) activation enhances recruitment of inflammatory macrophages and neutrophils to joints and promotes bone erosion in autoimmune arthritis; genetic deletion of Mdl1 or treatment with MDL-1-Ig fusion protein reduces clinical signs of joint inflammation.\",\n      \"method\": \"Mdl1 gene deletion (knockout mice), MDL-1-Ig fusion protein treatment, autoimmune arthritis model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus therapeutic blockade with defined cellular and pathological phenotype readouts\",\n      \"pmids\": [\"20212065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CLEC5A expression in monocytes/macrophages and granulocytes is transcriptionally regulated by the myeloid transcription factor PU.1, which binds directly to the CLEC5A promoter in vivo.\",\n      \"method\": \"Microarray profiling, PU.1 knockdown/restoration, CLEC5A promoter reporter assay, chromatin immunoprecipitation (ChIP) for PU.1 binding\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assay plus in vivo ChIP demonstrating direct PU.1 binding, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21094529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CLEC5A is homodimeric at the cell surface. A crystal structure (1.9 Å) revealed a β-sheet extension acting as a binary switch regulating molecular flexibility; extracellular conformational changes may be transmitted through the membrane to influence DAP12 signaling. CLEC5A binds dengue virus serotypes 1–4.\",\n      \"method\": \"X-ray crystallography (1.9 Å), molecular dynamics simulations, glycan microarray, docking studies, cell-surface binding experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by multiple complementary methods (MD simulation, glycan array, docking, binding assays) in single rigorous study\",\n      \"pmids\": [\"21566123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Activation of MDL-1 (CLEC5A) on immature CD11b+Gr-1+Ly6G+Ly6C+ myeloid cells triggers NO and TNF-α production via a DAP12/DAP10/Syk/PI3K/Akt/eNOS (not iNOS) signaling cascade, leading to shock; Akt physically interacts with and activates eNOS in this pathway.\",\n      \"method\": \"In vivo ConA liver injury model, MDL-1 agonist antibody treatment, MDL-1+ cell depletion, genetic knockouts, co-immunoprecipitation (Akt–eNOS interaction), pharmacological inhibition of Syk/PI3K/Akt\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus KO/depletion plus pharmacological pathway dissection, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22005300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CLEC5A is required for dengue virus-induced NLRP3 inflammasome activation and caspase-1-dependent IL-1β/IL-18 secretion and pyroptosis in GM-CSF-polarized (inflammatory) macrophages; blockade of CLEC5A inhibits NLRP3 inflammasome activation and pyroptosis.\",\n      \"method\": \"Anti-CLEC5A antibody blockade, caspase-1 activation assay, IL-1β/IL-18 ELISA, pyroptosis readout in GM-Mφ vs M-Mφ\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blockade with multiple downstream readouts (caspase-1, cytokines, cell death) in defined macrophage subsets, single lab but multiple orthogonal assays\",\n      \"pmids\": [\"23152543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CLEC5A interacts with the hemagglutinin protein of influenza viruses; CLEC5A-mediated signaling enhances proinflammatory cytokine (TNF-α, IP-10) production in macrophages without affecting viral replication; CLEC5A-deficient macrophages show elevated IFN-α and upregulated TLR3 after dsRNA treatment; CLEC5A-deficient mice show reduced lung inflammation and improved survival after lethal H5N1 challenge.\",\n      \"method\": \"Lectin screening identifying HA–CLEC5A interaction, siRNA silencing, anti-CLEC5A antibody blockade, Syk inhibitor, CLEC5A-KO mouse infection model\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (lectin screen, KD, antibody blockade, KO mice) identifying HA interaction and downstream signaling, single lab\",\n      \"pmids\": [\"27795434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dengue virus infection activates Nrf2 via PERK-mediated ER stress, which drives transcriptional upregulation of CLEC5A; elevated CLEC5A then enhances TLR3-independent TNF-α production; the DENV NS2B3 protein is sufficient to induce Nrf2 nuclear translocation and CLEC5A expression.\",\n      \"method\": \"Nrf2 nuclear translocation assay, PERK inhibition, CLEC5A promoter activation, NS2B3 forced expression, TNF-α ELISA, in vivo mouse brain analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (nuclear translocation, inhibitor, forced expression, in vivo) but single lab\",\n      \"pmids\": [\"27561946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dengue virus–CLEC5A interaction forms a multivalent hetero-complex with the mannose receptor (MR)/DC-SIGN on macrophages: MR/DC-SIGN first captures virus with high avidity, enabling low-avidity CLEC5A to engage virus in close proximity and initiate signaling.\",\n      \"method\": \"Co-immunoprecipitation, proximity-based binding assays, blocking experiments with anti-MR/DC-SIGN antibodies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown/co-IP evidence for hetero-complex formation, single lab, mechanistic model partly inferred from binding data\",\n      \"pmids\": [\"27832191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CLEC5A is required for neutrophil extracellular trap (NET) formation, ROS production, and proinflammatory cytokine (IL-1β, IL-17A, TNF) release in response to Listeria monocytogenes; Clec5a-/- mice show rapid bacterial dissemination, severe liver necrosis, and increased mortality, and CLEC5A engages bacterial peptidoglycan (GlcNAc/MurNAc disaccharides).\",\n      \"method\": \"Clec5a-/- mouse infection model, NET formation assay, ROS measurement, cytokine ELISA, liver histopathology, flow cytometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with multiple defined cellular phenotypes, bacterial load quantification, and histopathology; multiple orthogonal readouts\",\n      \"pmids\": [\"28824166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dengue virus activates platelets via CLEC2 to release extracellular vesicles (exosomes and microvesicles); these EVs activate CLEC5A and TLR2 on neutrophils and macrophages, inducing NET formation and proinflammatory cytokine release; simultaneous blockade of CLEC5A and TLR2 increases survival from 30% to 90% in dengue-infected stat1-/- mice.\",\n      \"method\": \"EV isolation and characterization, anti-CLEC5A/anti-TLR2 antibody blockade, NET formation assay, clec5a-/-/tlr2-/- double-KO mouse model, survival analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EV functional assay, double-KO mouse model, antibody blockade with defined phenotypic readouts, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31160588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SARS-CoV-2-activated platelets produce extracellular vesicles that induce NET formation via CLEC5A and TLR2 on neutrophils; simultaneous genetic ablation of CLEC5A and TLR2 (clec5a-/-/tlr2-/- mice) dramatically attenuates SARS-CoV-2-induced lung thromboinflammation in vivo.\",\n      \"method\": \"EV isolation from COVID-19 patient sera, anti-CLEC5A/anti-TLR2 antibody blockade, clec5a-/-/tlr2-/- double-KO mouse model, NET formation assay, in vivo lung inflammation assessment\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double-KO mouse model plus antibody blockade plus in vitro EV assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35820906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLEC5A mediates Zika virus-induced testicular inflammation; in clec5a-/-/stat1-/- mice, ZIKV-induced testicular inflammation, neutrophil infiltration, and sperm damage are reduced; CLEC5A-associated DAP12 signaling regulates ZIKV-induced testicular damage, as dap12-/-/stat1-/- mice phenocopy clec5a-/- mice.\",\n      \"method\": \"Clec5a-/- and dap12-/- KO mouse ZIKV infection model, immunohistochemistry, qRT-PCR for viral titer, cytokine measurement, spermatozoa counting/motility\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent KO mouse lines (CLEC5A and DAP12) with convergent phenotypes, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"36803804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-23 induces expansion of a myeloid MDL-1+CD11b+Ly6G+ osteoclast precursor population; genetic ablation of MDL-1 (CLEC5A) completely prevents IL-23-induced osteoclastogenesis and bone destruction in inflammatory arthritis; MDL-1-/- mice have increased bone mineral density.\",\n      \"method\": \"In vivo IL-23 gene transfer, spectral flow cytometry, micro-CT bone analysis, Western blotting, immunoprecipitation, MDL-1-KO mouse osteoclastogenesis assay\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model plus in vivo gene transfer plus multiple bone phenotype readouts, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36787107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MDL-1 (CLEC5A) on osteoclast precursors is upregulated during intestinal inflammation; anti-MDL-1 antibody treatment abrogates enhanced osteoclast differentiation ex vivo and ameliorates bone loss during colitis in vivo.\",\n      \"method\": \"Multiple murine colitis models, anti-MDL-1 antibody treatment, ex vivo osteoclast differentiation assay, flow cytometry, micro-CT\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — therapeutic antibody blockade plus ex vivo functional assay plus multiple in vivo models with defined skeletal phenotype\",\n      \"pmids\": [\"35835390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endothelial CLEC5A drives vascular barrier dysfunction in sepsis; endothelial-specific knockdown of CLEC5A improves survival and reduces vascular leakage in CLP-challenged mice; in vitro, CLEC5A deletion maintains trans-endothelial electrical resistance and inhibits monocyte/neutrophil adhesion and trans-endothelial migration under LPS stimulation.\",\n      \"method\": \"Endothelial-specific CLEC5A knockdown, CLEC5A re-expression rescue, CLP sepsis mouse model, single-cell RNA sequencing, trans-endothelial electrical resistance assay, monocyte/neutrophil adhesion and migration assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KD with rescue experiment plus in vitro barrier assays plus in vivo survival model, multiple orthogonal methods\",\n      \"pmids\": [\"40498836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CLEC5A knockdown in a myocardial infarction model suppresses macrophage M1 polarization, NLRP3 inflammasome activation, pyroptosis, and NF-κB signaling in the left ventricle; in vitro, CLEC5A knockdown inhibits LPS/IFNγ-stimulated M1 polarization in RAW264.7 cells and blocks polarized macrophage-induced NLRP3/pyroptosis in co-cultured cardiomyocytes.\",\n      \"method\": \"In vivo adenoviral shRNA knockdown, mouse MI model, in vitro co-culture, Western blot for NLRP3/caspase-1/NF-κB, macrophage polarization assay\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with multiple downstream readouts but single lab, no KO rescue experiment\",\n      \"pmids\": [\"33939927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Clec5a knockout microglia show enhanced phagocytosis of Aβ; in AD mice, Clec5a knockout reduces Aβ deposition, increases microglia coverage around plaques, and ameliorates memory deficits; CLEC5A normally restrains microglial Aβ clearance.\",\n      \"method\": \"Clec5a-/- × AD mouse model crosses, Morris water maze, ELISA for Aβ, immunohistochemistry, fluorescent-labeled Aβ phagocytosis assay in knockdown microglial lines and KO primary microglia\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model plus in vitro phagocytosis assay, multiple readouts, single lab\",\n      \"pmids\": [\"39443966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CLEC5A interacts with TREM1; this interaction mediates NLRC4 expression and thereby promotes neuronal pyroptosis in a spinal cord injury model; knockdown of CLEC5A, TREM1, or NLRC4 attenuates pyroptosis markers (LDH, GSDMD-N, caspase-1, IL-1β, IL-18).\",\n      \"method\": \"Co-immunoprecipitation (CLEC5A–TREM1 interaction), siRNA knockdown in PC12 cells and in vivo rat SCI model, Western blot for pyroptosis markers\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP identifying CLEC5A–TREM1 interaction, knockdown phenotype supports functional link, single lab\",\n      \"pmids\": [\"39187376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLEC5A epigenetic upregulation via DNMT1-mediated demethylation of CpG site cg06744540 drives CLEC5A overexpression in monocytes/macrophages; elevated CLEC5A activates NF-κB signaling to enhance inflammation, migration, adhesion, macrophage polarization, lipid accumulation, and inhibit apoptosis; folic acid increases DNMT1 expression, reduces CLEC5A, and suppresses atherosclerotic plaque formation in vivo.\",\n      \"method\": \"Methylome–transcriptome integration, DNMT1 overexpression, CpG site mapping, NF-κB pathway analysis, functional assays (migration, adhesion, lipid accumulation), high-fat ApoE-/- mouse model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic mapping plus functional rescue with DNMT1/folic acid plus in vivo model, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40147659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In tolerogenic dendritic cells (tolDCs), Clec5a promotes IL-10 production and Foxp3+ Treg induction while suppressing NF-κB signaling and IL-6; Clec5a-knockdown tolDCs show reduced immunomodulatory function; administration of Clec5a-expressing DCs ameliorates dopaminergic neuron loss, reduces α-synuclein accumulation, and improves locomotor behavior in MPTP-induced PD mice.\",\n      \"method\": \"Clec5a knockdown in tolDCs, cytokine ELISA (IL-10, IL-6), Foxp3+ Treg quantification, NF-κB signaling assay, MPTP mouse model, immunohistochemistry\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD in tolDCs with defined cytokine readouts plus in vivo rescue, single lab, single study\",\n      \"pmids\": [\"40917058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CLEC5A binds fucose and mannose moieties of dengue virus membrane glycans, as well as GlcNAc/MurNAc disaccharides of bacterial cell walls, establishing its dual ligand-recognition properties as a pattern recognition receptor.\",\n      \"method\": \"Glycan binding assays, structural analyses reviewed in the context of prior crystallography and binding studies\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review synthesizing multiple prior experimental binding studies; carbohydrate specificity established by prior glycan array (PMID 21566123) and bacterial studies (PMID 28824166)\",\n      \"pmids\": [\"32152943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2059,\n      \"finding\": \"REEP5 physically binds CLEC5A and its overexpression abolishes CLEC5A-induced ER stress-mediated apoptosis in cardiomyocytes, placing REEP5 as a negative regulator of CLEC5A-driven cardiac cell death.\",\n      \"method\": \"Co-immunoprecipitation (REEP5–CLEC5A interaction), REEP5 overexpression in hypoxia-induced cardiomyocyte model, ER stress markers (PERK, IRE1α, ATF6, CHOP, caspase-12), in vivo MI mouse model\",\n      \"journal\": \"BMC cardiovascular disorders\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP interaction claim, single lab, mechanistic context derived from overexpression without KO validation\",\n      \"pmids\": [\"39044150\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLEC5A (MDL-1/CLECSF5) is a type II transmembrane C-type lectin on myeloid cells (monocytes, macrophages, neutrophils, dendritic cells) and endothelial cells that signals through a non-covalent association with the ITAM-bearing adaptor DAP12 (and cooperatively with DAP10), activating a Syk/PI3K/Akt cascade; it acts as a pattern recognition receptor for flavivirus glycans (via terminal fucose/mannose), bacterial peptidoglycan (GlcNAc/MurNAc), and platelet-derived extracellular vesicles (via TLR2 co-engagement), driving proinflammatory cytokine production, NLRP3 inflammasome activation, NET formation, osteoclastogenesis, and vascular barrier dysfunction, while its transcription is controlled by PU.1 and by Nrf2 during viral infection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLEC5A (MDL-1/CLECSF5) is a type II transmembrane C-type lectin on myeloid and endothelial cells that functions as a pattern-recognition receptor coupling pathogen and damage signals to proinflammatory myeloid activation [#0, #1]. It lacks an intrinsic signaling motif and instead transduces signals through non-covalent association with the ITAM-bearing adaptor DAP12 via a charged transmembrane residue, with cooperative recruitment of DAP10, triggering calcium mobilization and a Syk/PI3K/Akt cascade that in immature myeloid cells drives NO and TNF-\\u03b1 production through Akt-activated eNOS [#0, #2, #6]. As a receptor, homodimeric CLEC5A recognizes terminal fucose/mannose glycans on flavivirus virions, influenza hemagglutinin, and GlcNAc/MurNAc disaccharides of bacterial peptidoglycan, and engages platelet-derived extracellular vesicles in concert with TLR2 [#5, #8, #11, #12, #23]. Through these ligands CLEC5A drives proinflammatory cytokine release, NLRP3 inflammasome activation and pyroptosis, neutrophil extracellular trap formation, and vascular barrier dysfunction across dengue, Zika, influenza, SARS-CoV-2, bacterial, and sepsis models, where its genetic or antibody-mediated blockade reduces inflammation and improves survival [#1, #7, #11, #12, #13, #17]. CLEC5A additionally promotes osteoclastogenesis and inflammatory bone erosion in arthritis and colitis, and its transcription is controlled by the myeloid factor PU.1 and induced by Nrf2 during viral infection [#2, #3, #15, #16, #4, #9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established CLEC5A as a myeloid activating receptor by showing it has no intrinsic signaling capacity but couples to the ITAM adaptor DAP12 to mobilize calcium, defining the core signaling logic.\",\n      \"evidence\": \"Molecular cloning, co-association assay and calcium mobilization in J774 macrophages\",\n      \"pmids\": [\"10449773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand unknown at this stage\", \"Downstream effector cascade beyond calcium not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the first physiological context for CLEC5A as a flavivirus sensor, showing direct dengue virion binding triggers DAP12 phosphorylation and pathogenic cytokine release driving plasma leakage in vivo.\",\n      \"evidence\": \"Direct binding assay, DAP12 phosphorylation, anti-CLEC5A blockade and STAT1-deficient mouse model\",\n      \"pmids\": [\"18496526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise glycan ligand on virion not yet resolved\", \"Cofactor requirements for low-avidity engagement unaddressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Expanded the receptor complex to a trimolecular MDL-1\\u2013DAP12/DAP10 assembly and linked CLEC5A signaling to osteoclastogenesis, broadening its role beyond infection to bone homeostasis.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro osteoclastogenesis and DAP10-knockout mouse phenotyping\",\n      \"pmids\": [\"19251634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand driving osteoclast-context activation unclear\", \"Relative signaling contributions of DAP12 vs DAP10 not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated CLEC5A as a pathogenic driver of inflammatory arthritis and defined its transcriptional control by PU.1, connecting receptor expression to myeloid lineage programming.\",\n      \"evidence\": \"Mdl1 knockout and MDL-1-Ig blockade in arthritis model; ChIP and promoter reporter for PU.1 binding\",\n      \"pmids\": [\"20212065\", \"21094529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous arthritis-relevant ligand not identified\", \"Additional transcriptional regulators not explored\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided structural and mechanistic detail by solving the crystal structure revealing a homodimer with a conformational binary switch, and dissected the DAP12/DAP10/Syk/PI3K/Akt/eNOS cascade leading to shock.\",\n      \"evidence\": \"X-ray crystallography with MD/glycan array/docking; in vivo ConA liver injury with co-IP and pharmacological pathway dissection\",\n      \"pmids\": [\"21566123\", \"22005300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How extracellular conformational change is transmitted to DAP12 not directly demonstrated\", \"eNOS-vs-iNOS branching context dependence incompletely mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked CLEC5A to inflammasome biology by showing it is required for dengue-induced NLRP3 activation, caspase-1-dependent IL-1\\u03b2/IL-18 release and pyroptosis selectively in inflammatory macrophages.\",\n      \"evidence\": \"Anti-CLEC5A blockade, caspase-1 and cytokine assays in GM-CSF vs M-CSF macrophages\",\n      \"pmids\": [\"23152543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between CLEC5A signaling and NLRP3 assembly not resolved\", \"Reason for macrophage-subset specificity unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened ligand recognition to influenza hemagglutinin and defined how viral infection feeds back to upregulate CLEC5A via PERK/Nrf2 ER stress, and how virus engages CLEC5A cooperatively with MR/DC-SIGN.\",\n      \"evidence\": \"Lectin screen, siRNA/blockade and CLEC5A-KO H5N1 infection; Nrf2 translocation and NS2B3 forced expression; co-IP and proximity binding with MR/DC-SIGN\",\n      \"pmids\": [\"27795434\", \"27561946\", \"27832191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MR/DC-SIGN hetero-complex model partly inferred from binding data\", \"Nrf2 axis from single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established CLEC5A as a bacterial sensor recognizing peptidoglycan GlcNAc/MurNAc and required for NET formation and antibacterial defense, generalizing its pattern-recognition role beyond viruses.\",\n      \"evidence\": \"Clec5a-/- Listeria infection model with NET, ROS, cytokine and histopathology readouts\",\n      \"pmids\": [\"28824166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of disaccharide recognition not solved\", \"Contribution to other bacterial infections untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a platelet\\u2013EV\\u2013CLEC5A/TLR2 axis whereby virus-activated platelets release vesicles that co-engage CLEC5A and TLR2 to drive NETosis, and consolidated dual carbohydrate ligand specificity.\",\n      \"evidence\": \"EV functional assays, dual antibody blockade and clec5a-/-/tlr2-/- double-KO dengue mouse survival; review of glycan specificity\",\n      \"pmids\": [\"31160588\", \"32152943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EV cargo recognized by CLEC5A not identified\", \"Mechanism of CLEC5A\\u2013TLR2 cooperation undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the EV/CLEC5A/TLR2 NETosis axis to SARS-CoV-2 thromboinflammation and demonstrated CLEC5A as the essential driver of IL-23-induced and colitis-associated osteoclastogenesis and bone destruction.\",\n      \"evidence\": \"clec5a-/-/tlr2-/- COVID lung inflammation model; IL-23 gene transfer with micro-CT and MDL-1-KO; colitis models with anti-MDL-1 antibody\",\n      \"pmids\": [\"35820906\", \"36787107\", \"35835390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same EV ligands operate across diseases unconfirmed\", \"Direct osteoclast-precursor activating ligand unidentified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed DAP12 as the obligate signaling partner for CLEC5A-driven tissue pathology in vivo by showing dap12-/- mice phenocopy clec5a-/- mice in Zika-induced testicular inflammation.\",\n      \"evidence\": \"Clec5a-/- and dap12-/- ZIKV infection models with histology, viral titer and sperm function readouts\",\n      \"pmids\": [\"36803804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan ligand on ZIKV not specified\", \"Cell type initiating testicular damage not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an endothelial role for CLEC5A in vascular barrier dysfunction and an epigenetic mechanism (DNMT1/CpG demethylation) driving monocyte CLEC5A overexpression and NF-\\u03baB-dependent atherogenic inflammation.\",\n      \"evidence\": \"Endothelial-specific knockdown with rescue in CLP sepsis plus barrier/adhesion assays; methylome\\u2013transcriptome integration with DNMT1/folic acid in ApoE-/- model\",\n      \"pmids\": [\"40498836\", \"40147659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endothelial CLEC5A ligand and DAP12 dependence in endothelium not defined\", \"Atherosclerosis epigenetic axis from single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed context-dependent and tissue-protective or regulatory roles for CLEC5A, including restraint of microglial A\\u03b2 clearance, a TREM1\\u2013NLRC4 pyroptosis axis, and tolerogenic DC immunomodulation.\",\n      \"evidence\": \"Clec5a-/- AD crosses with phagocytosis assays; CLEC5A\\u2013TREM1 co-IP and knockdown in SCI; Clec5a knockdown tolDCs in PD model\",\n      \"pmids\": [\"39443966\", \"39187376\", \"40917058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CLEC5A\\u2013TREM1 interaction rests on single co-IP without reciprocal validation\", \"Mechanism of A\\u03b2 clearance restraint not defined\", \"tolDC immunomodulation from single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How extracellular ligand binding and the homodimer conformational switch are mechanistically transmitted across the membrane to control DAP12/DAP10 ITAM signaling, and whether distinct ligands evoke distinct downstream programs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of a CLEC5A\\u2013DAP12 signaling complex\", \"Ligand-specific signaling outcomes not directly compared\", \"Determinants of pro- vs anti-inflammatory outcomes in different tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [1, 11, 12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 7, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 18, 20]}\n    ],\n    \"complexes\": [\n      \"CLEC5A\\u2013DAP12 complex\",\n      \"CLEC5A\\u2013DAP12\\u2013DAP10 trimolecular complex\"\n    ],\n    \"partners\": [\n      \"DAP12\",\n      \"DAP10\",\n      \"TLR2\",\n      \"TREM1\",\n      \"REEP5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}