Affinage

SPINK5

Serine protease inhibitor Kazal-type 5 · UniProt Q9NQ38

Length
1064 aa
Mass
120.7 kDa
Annotated
2026-06-10
100 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPINK5 encodes LEKTI, a multi-domain Kazal-type serine protease inhibitor that governs epidermal desquamation and skin barrier homeostasis by restraining kallikrein-mediated proteolysis (PMID:17596512, PMID:11943586). LEKTI is synthesized as high-molecular-weight precursors from three alternatively spliced transcripts (15-domain, 13-domain, and a 30-amino-acid-insertion isoform) and is rapidly cleaved by furin at multiple sites into single- and multi-domain secreted fragments (PMID:12915442, PMID:16374478). These fragments display domain-selective, pH-dependent inhibition of the epidermal kallikreins KLK5, KLK7, and KLK14: multidomain fragments such as D8-D11 and domains 6-12 bind the trypsin-like KLK5 with near-irreversible, nanomolar affinity that is released under the acidic pH of the stratum corneum, while only the domain 6-9' fragment inhibits the chymotrypsin-like KLK7, providing a pH- and layer-dependent switch for protease activity (PMID:17596512, PMID:16307483, PMID:17989726). Spatially, LEKTI is stored in lamellar granules and secreted into the stratum granulosum ahead of and physically separated from its target kallikreins, ensuring inhibition is engaged only at the appropriate epidermal layer (PMID:15675955). By limiting kallikrein activity, LEKTI protects corneodesmosomal proteins desmoglein-1 and desmocollin-1 from degradation; loss-of-function SPINK5 mutations cause Netherton syndrome, in which unchecked serine protease activity degrades these structural proteins and the magnitude of activation scales with barrier-defect severity (PMID:16601670, PMID:22730493). Reintroduction of SPINK5 into patient keratinocytes restores LEKTI expression, protease inhibition, and epidermal architecture, confirming the gene's causal role (PMID:20877344, PMID:21251800). A common E420K variant redirects furin cleavage to prevent formation of the most potent anti-KLK5 fragment, enhancing kallikrein and elastase activity, accelerating desmoglein-1 and profilaggrin proteolysis, and inducing the proallergic cytokine TSLP (PMID:22730493). Beyond the epidermis, SPINK5 has been reported to act as a tumor suppressor that restrains Wnt/β-catenin signaling in esophageal cancer and STAT3 signaling in melanoma (PMID:30868765, PMID:35705923).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 Medium

    Established LEKTI as a 15-domain Kazal-type serine protease inhibitor with intrinsic protease-inhibitory activity, defining the molecular class of the protein.

    Evidence Protein isolation from blood filtrate, cDNA cloning, and in vitro trypsin inhibition with recombinant domains

    PMID:11943586

    Open questions at the time
    • Physiological target proteases not identified
    • No connection to epidermal biology yet established
    • Most of the 15 domains untested for activity
  2. 2003 High

    Identified furin as the processing protease that converts the LEKTI precursor into secreted C-terminal fragments, defining how the inhibitor is matured.

    Evidence Western blot of keratinocyte isoforms, furin inhibitor treatment, and in vitro furin cleavage of recombinant precursor

    PMID:12915442

    Open questions at the time
    • Functional differences among fragments not resolved
    • Target proteases of each fragment not yet defined
  3. 2004 High

    Demonstrated domain-specific and mechanistically distinct inhibition, showing different LEKTI fragments inhibit different proteases by competitive vs noncompetitive modes.

    Evidence Baculovirus-expressed recombinant fragments with kinetic Ki and inhibition-mechanism assays against trypsin, subtilisin, plasmin, cathepsin G, elastase

    PMID:15039071

    Open questions at the time
    • Tested proteases are not the principal epidermal kallikreins
    • Physiological relevance of each target not established
  4. 2005 High

    Defined the differential domain selectivity for the desquamation kallikreins KLK5 vs KLK7 and the pH-dependence of binding, linking LEKTI to epidermal protease regulation.

    Evidence In vitro inhibition kinetics with recombinant LEKTI fragments and KLK5/KLK7 at pH 5.0 and 8.0, plus subcellular localization by confocal and immunoelectron microscopy

    PMID:15675955 PMID:16307483

    Open questions at the time
    • KLK14 not yet included
    • In vivo timing of secretion inferred, not directly measured
    • Substrate consequences of unchecked kallikreins not yet shown
  5. 2006 Medium

    Connected LEKTI loss to corneodesmosome destruction in Netherton syndrome, identifying DSG1/DSC1 as the kallikrein substrates whose degradation drives the barrier defect.

    Evidence Serine protease activity assays, in situ zymography, and desmosomal protein western blots in phenotype-stratified NS patient biopsies

    PMID:16601670

    Open questions at the time
    • Causality from patient correlation only
    • Compensatory DSG3/DSC3 mechanism not mechanistically dissected
  6. 2006 Medium

    Showed alternative splicing yields three LEKTI isoforms each generating distinct secreted fragments, expanding the diversity of bioactive inhibitors.

    Evidence RT-PCR transcript characterization and western blot of isoform proteins and secreted fragments in differentiated keratinocytes

    PMID:16374478

    Open questions at the time
    • Functional differences between isoform-derived fragments not quantified
    • Tissue-specific isoform regulation unknown
  7. 2007 High

    Resolved the mechanism by which the epidermal pH gradient regulates kallikrein activity, showing acidic pH releases active KLK5 from the most potent D8-D11 fragment.

    Evidence Furin inhibitor treatment, antibody fragment mapping, and pH-dependent binding/release kinetics in keratinocytes

    PMID:17596512

    Open questions at the time
    • KLK14 regulation less characterized
    • In vivo pH-dependent release in stratum corneum inferred from in vitro kinetics
  8. 2007 Medium

    Mapped genotype-phenotype correlations and domain-resolved protease specificity, linking LEKTI truncation length to clinical severity.

    Evidence Recombinant domain fragments tested against stratum corneum protease activities, KLK ELISA in patient samples, and clinical correlation in Japanese NS patients

    PMID:17989726

    Open questions at the time
    • Correlative, not causal, link between domain length and phenotype
    • Single population cohort
  9. 2010 Medium

    Provided causal proof that restoring SPINK5/LEKTI corrects the Netherton phenotype, validating the gene as the disease driver and therapeutic target.

    Evidence Lentiviral and AAV2 gene transfer into NS keratinocytes with organotypic culture, skin grafting, and hydrolytic protease-inhibition assays

    PMID:20877344 PMID:21251800

    Open questions at the time
    • Single-lab model systems
    • Durability and safety of correction in vivo not addressed
  10. 2011 High

    Defined the precise proteolytic cascade and quantified LEKTI-to-KLK5 ratios in vivo, establishing that fragment generation supports fine-tuned inhibition.

    Evidence Antibody mapping, N-terminal sequencing, site-specific mutagenesis, and quantitative western blot of epidermal extracts

    PMID:21697885

    Open questions at the time
    • Regulation of cascade ordering not fully resolved
    • In vivo spatial dynamics of intermediates not visualized
  11. 2012 High

    Mechanistically explained the atopic-dermatitis-associated E420K variant, showing it reroutes furin cleavage to abolish the most potent anti-KLK5 fragment and amplify proteolysis and TSLP induction.

    Evidence In vitro furin cleavage assays, in situ and gel zymography, DSG1/profilaggrin western blots, and TSLP immunostaining in 420KK epidermis

    PMID:22730493

    Open questions at the time
    • Population-level penetrance of variant not addressed
    • Link from TSLP induction to clinical atopy not directly tested
  12. 2016 Medium

    Showed LEKTI upregulation acts as a compensatory brake in atopic dermatitis, where impaired KLK7 secretion and elevated LEKTI keep net protease activity in check.

    Evidence In situ zymography on tape-stripped corneocytes, electron microscopy of lamellar granule secretion, and LEKTI immunostaining in AD lesional skin

    PMID:27769847

    Open questions at the time
    • Trigger for compensatory LEKTI upregulation unknown
    • Single-lab patient cohort
  13. 2022 Medium

    Extended SPINK5 function beyond the epidermis, placing it as a target of miR-5100 that restrains STAT3 signaling and melanoma metastasis.

    Evidence Luciferase reporter for miR-5100 targeting, STAT3 phosphorylation western blots, Co-IP, and in vivo lung metastasis model with metformin

    PMID:35705923

    Open questions at the time
    • SPINK5-STAT3 interaction described as indirect, not mapped
    • Mechanism linking a secreted protease inhibitor to intracellular STAT3 unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a secreted Kazal-type protease inhibitor mechanistically engages intracellular signaling cascades (Wnt/β-catenin, STAT3) to act as a tumor suppressor remains unresolved.
  • No direct molecular link between LEKTI and intracellular signaling components
  • Reported interactions are indirect Co-IP only
  • No structural or mutagenesis basis for the proposed signaling mechanisms

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140313 molecular sequestering activity 2
Localization
GO:0005576 extracellular region 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 3
Partners
DSG1FURINKLK14KLK5KLK7

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 LEKTI is produced as a precursor that is rapidly cleaved by furin at multiple sites, generating a variety of single or multidomain secreted fragments (D1, D5, D6, D8-D11, D9-D15) in keratinocytes and epidermis. All fragments except D1 specifically inhibit KLK5, KLK7, and KLK14. The D8-D11 fragment shows the strongest inhibition of KLK5 via a rapid, tight (near-irreversible) interaction. This KLK5-LEKTI interaction is pH-dependent: at acidic pH, active KLK5 is released from the complex, providing a mechanism by which the epidermal pH gradient regulates KLK5 activity and corneodesmosomal cleavage in the stratum corneum. Furin inhibitor treatment in cultured keratinocytes, biochemical antibody panel mapping of secreted fragments, kinetic analysis of inhibition (Ki, kass, kdis), pH-dependent binding/release assays Molecular biology of the cell High 17596512
2003 LEKTI is expressed as a 145 kDa full-length protein and a 125 kDa isoform in differentiated human primary keratinocytes; both are N-glycosylated and processed post-ER into C-terminal fragments of 42, 65, and 68 kDa that are secreted. Processing is blocked by a furin inhibitor, and in vitro cleavage of the recombinant 145 kDa precursor by furin generates the 65 and 68 kDa C-terminal fragments, establishing furin as the processing protease. Western blot with monoclonal/polyclonal antibodies, furin inhibitor treatment, in vitro furin cleavage of recombinant LEKTI precursor, N-glycosylation analysis Human molecular genetics High 12915442
2005 In normal human epidermis, LEKTI is localized within lamellar granules (LGs) but is spatially separated from KLK7 and KLK5 within that compartment. LEKTI is expressed and secreted into extracellular spaces of the superficial stratum granulosum earlier than KLK7 and KLK5, suggesting the LG system uses differential timing of secretion to prevent premature degradation of stratum corneum by sequestering the inhibitor from its targets until the appropriate epidermal layer is reached. Confocal laser scanning microscopy and immunoelectron microscopy with co-localization analysis in normal vs. Netherton syndrome skin The Journal of investigative dermatology High 15675955
2005 Recombinant LEKTI fragments containing domains 6-8 and 9-12 are potent inhibitors of kallikrein KLK5 (a trypsin-like protease) with Ki of 1.2–5.5 nM at pH 8.0 and 10–20 nM at pH 5.0; dissociation half-life is 20–25 min indicating tight, specific binding. Only fragment 6-9' (not 9-12) inhibits KLK7 (a chymotrypsin-like protease) with Ki of 11 nM at pH 8.0 in a rapidly reversible manner, establishing differential domain selectivity for KLK5 vs KLK7. In vitro enzyme inhibition kinetics with recombinant LEKTI fragments and recombinant KLK5/KLK7; measurement of Ki, kass, kdis at pH 8.0 and pH 5.0 Biological chemistry High 16307483
2006 In Netherton syndrome patient skin, the magnitude of serine protease activation correlates with barrier defect severity and inversely with residual LEKTI expression. LEKTI co-localizes with KLK5 and KLK7 in the stratum corneum and inhibits both. Excess serine protease activity causes loss of corneodesmosomes via KLK-mediated degradation of desmoglein 1 (DSG1) and desmocollin 1 (DSC1), while compensatory upregulation of DSG3/DSC3 maintains nucleated epidermal integrity. Serine protease activity assays, LEKTI immunostaining, in situ zymography, western blot for desmosomal proteins in NS patient biopsies stratified by phenotype severity The Journal of investigative dermatology Medium 16601670
2011 LEKTI is synthesized from three distinct high-molecular-weight precursors that undergo a defined proteolytic cascade in the epidermis. Antibody mapping, N-terminal sequencing, and site-specific mutagenesis defined the amino acid sequences of the physiologically generated LEKTI polypeptides and three novel processing intermediates. The most effective fragments against desquamation-related kallikreins (KLK5, KLK7) were identified; LEKTI polypeptides inhibit KLK-mediated proteolysis of desmoglein-1, and quantification shows ratios of LEKTI polypeptides to active KLK5 in the uppermost epidermis are compatible with fine-tuned inhibition. Antibody mapping, N-terminal sequencing, site-specific mutagenesis, in vitro inhibition assays, quantitative western blot of epidermal extracts The Journal of investigative dermatology High 21697885
2012 The common SPINK5 variant E420K (Glu420Lys) increases the likelihood of furin-dependent cleavage of the LEKTI precursor within the D6-D7 linker region, reversing the cleavage priority for LEKTI activation and preventing formation of the D6D9 fragment, which has the strongest inhibitory activity against KLK5-mediated desmoglein-1 (DSG1) degradation. In 420KK epidermis, KLK5, KLK7, and elastase-2 activities are enhanced, DSG1 expression is reduced, and profilaggrin proteolysis is accelerated. Additionally, 420KK epidermis shows increased expression of the proallergic cytokine TSLP. In vitro furin cleavage assays, in situ and gel zymographies for protease activity, immunohistochemistry, western blot for DSG1 and profilaggrin, TSLP immunostaining in patient epidermis Human molecular genetics High 22730493
2004 Recombinant LEKTI domains 6-9' inhibit trypsin (Ki = 356 nM) and subtilisin A (Ki = 193 nM) by a noncompetitive mechanism, whereas recombinant LEKTI domain 6 alone does not inhibit subtilisin A but competitively inhibits trypsin (Ki = 200 nM). Full-length LEKTI inhibits plasmin, cathepsin G, and elastase but domains 6-9' do not, demonstrating domain-specific inhibitory activity. Baculovirus expression and purification of recombinant LEKTI fragments; enzyme inhibition kinetics determining Ki and inhibition mechanism Protein expression and purification High 15039071
2006 SPINK5 generates three classes of alternatively spliced transcripts encoding three LEKTI isoforms: a 15-domain isoform, a 13-domain isoform, and a longer isoform with a 30-amino acid insertion between domains 13 and 14. In differentiated human keratinocytes, all three LEKTI isoforms are translated into protein, and each precursor generates distinct secreted C-terminal proteolytic fragments from similar cleavage sites, providing an additional mechanism for diversifying bioactive LEKTI fragments. RT-PCR characterization of alternative transcripts, western blot detection of isoform proteins in differentiated keratinocytes, identification of secreted C-terminal fragments The Journal of investigative dermatology Medium 16374478
2002 LEKTI is a 15-domain Kazal-type serine proteinase inhibitor isolated from human blood filtrate. Two of the 15 domains closely match the classical Kazal-type pattern (with 6 Cys), while 13 domains have only 4 Cys. Three recombinant LEKTI domains were shown to have significant trypsin-inhibiting activity. Protein isolation from blood filtrate, cDNA cloning, domain structure analysis, in vitro trypsin inhibition assay with recombinant domains The international journal of biochemistry & cell biology Medium 11943586
2010 Lentiviral gene transfer of SPINK5 into Netherton syndrome keratinocytes restores LEKTI expression and corrects epidermal architecture in organotypic cultures and in vivo mouse/human skin grafts. Even partial restoration of LEKTI expression in limited cell numbers confers a broader bystander benefit, consistent with LEKTI acting as a secreted inhibitor that can diffuse to neighboring cells. HIV-1-based lentiviral vector transduction of NS keratinocytes, organotypic culture, mouse/human skin engraftment model, immunofluorescence for LEKTI expression and epidermal architecture Molecular therapy Medium 20877344
2010 AAV2-mediated gene transfer of full-length SPINK5 cDNA into LEKTI-deficient NS keratinocytes produces a five-fold increase in SPINK5 mRNA reaching ~75% of normal, and restored LEKTI protein demonstrates serine protease inhibitory activity in a hydrolytic activity assay at levels approaching those of healthy keratinocytes. rAAV2 transduction, RT-PCR for mRNA quantification, hydrolytic activity assay for LEKTI function in transduced vs. normal keratinocytes Journal of dermatological science Medium 21251800
2007 Genotype-phenotype correlations in Japanese NS patients show that LEKTI truncation length correlates with cutaneous severity, growth retardation, and skin infection. Using recombinant LEKTI proteins of varying domain length, trypsin-like (Phe-Ser-Arg-) protease activity in stratum corneum is predominantly inhibited by LEKTI domains 6-12, plasmin- and trypsin-like (Pro-Phe-Arg-) activities by domains 12-15, and chymotrypsin-like activity by all domains; furin-like activity is not inhibited by any domain. KLK5 and KLK7 levels are significantly elevated in NS patient stratum corneum and serum. Recombinant LEKTI domain expression and stratum corneum protease activity assays with fluorogenic substrates; KLK ELISA in patient samples; clinical correlation analysis The Journal of investigative dermatology Medium 17989726
2016 In atopic dermatitis lesional skin, KLK7 secretion from lamellar granules is impaired, and LEKTI expression is upregulated compared to normal skin. KLK activity measured by in situ zymography on tape-stripped corneocytes is not significantly elevated in AD lesions despite increased KLK7 protein, indicating that elevated LEKTI expression constitutes a compensatory mechanism preventing further barrier dysfunction by suppressing KLK activity. Western blot for corneodesmosin degradation patterns, in situ zymography on tape-stripped corneocytes, electron microscopy and immunostaining for KLK7 secretion from lamellar granules, LEKTI immunostaining The Journal of investigative dermatology Medium 27769847
2019 SPINK5 overexpression in esophageal cancer cells inhibits the Wnt/β-catenin signaling pathway: SPINK5 inhibits GSK3β phosphorylation and promotes β-catenin protein degradation (confirmed with LiCl or MG-132 co-treatment), reducing cell proliferation, migration, and invasion. Co-immunoprecipitation suggested an indirect interaction between SPINK5 and components of this pathway. In vivo, SPINK5 overexpression significantly inhibits esophageal cancer cell growth in a xenograft model. Western blot for Wnt/β-catenin pathway components, LiCl/MG-132 pharmacological rescue experiments, in vivo xenograft model, bioinformatics pathway analysis Cancer medicine Low 30868765
2022 miR-5100 directly targets SPINK5 (confirmed by luciferase reporter assay), reducing SPINK5 expression and thereby activating STAT3 phosphorylation in melanoma cells. Reduced SPINK5 promotes epithelial-mesenchymal transition and melanoma metastasis. Co-immunoprecipitation confirmed an indirect interaction between SPINK5 and STAT3. Metformin suppresses the miR-5100/SPINK5/STAT3 axis, reducing melanoma cell metastasis to lung in a mouse model. Luciferase reporter assay for miR-5100 targeting SPINK5, western blot for STAT3 phosphorylation, migration/wound healing assays, co-immunoprecipitation for SPINK5-STAT3 interaction, in vivo mouse lung metastasis model Cellular & molecular biology letters Medium 35705923
2019 Compound K (an active ginsenoside metabolite) increases SPINK5 gene promoter activity and SPINK5/LEKTI protein expression in UVB-irradiated HaCaT keratinocytes, resulting in decreased downstream KLK5, KLK7, and PAR2 expression. In UVB-irradiated mouse and DNCB-induced atopic dermatitis mouse models, CK treatment restores SPINK5 expression and normalizes the expression of desquamation-related proteins. Transactivation (promoter activity) assay, RT-PCR, western blot, mouse models with TEWL and histology readouts Journal of ginseng research Low 33192123

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Insecticide-treated bed nets and curtains for preventing malaria. The Cochrane database of systematic reviews 1028 15106149
2005 Flexible nets. The roles of intrinsic disorder in protein interaction networks. The FEBS journal 935 16218947
2013 Thrombosis: tangled up in NETs. Blood 687 24366358
2019 DAMPs and NETs in Sepsis. Frontiers in immunology 507 31736963
2021 A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics. Clinical reviews in allergy & immunology 499 32740860
2020 The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis. Frontiers in immunology 442 33042107
1998 Perineuronal nets: past and present. Trends in neurosciences 416 9881847
2021 Perineuronal nets stabilize the grid cell network. Nature communications 303 33431847
2007 LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Molecular biology of the cell 237 17596512
2020 Neutrophil Extracellular Traps (NETs) Take the Central Stage in Driving Autoimmune Responses. Cells 225 32276504
2021 Neutrophil Extracellular Traps (NETs) in Cancer Invasion, Evasion and Metastasis. Cancers 201 34503307
2016 The Emerging Role of NETs in Venous Thrombosis and Immunothrombosis. Frontiers in immunology 195 27446071
2018 Insecticide-treated nets for preventing malaria. The Cochrane database of systematic reviews 170 30398672
2020 Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression. Advances in biological regulation 166 32773102
2013 Neutrophil extracellular traps (NETs) - formation and implications. Acta biochimica Polonica 166 23819131
2003 LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Human molecular genetics 162 12915442
2022 Neutrophil Extracellular Traps (NETs) and Covid-19: A new frontiers for therapeutic modality. International immunopharmacology 157 35032828
2015 Simplified Human Neutrophil Extracellular Traps (NETs) Isolation and Handling. Journal of visualized experiments : JoVE 151 25938591
2002 Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. The Journal of investigative dermatology 144 11841556
2019 Untangling "NETosis" from NETs. European journal of immunology 140 30629284
2003 Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. The British journal of dermatology 136 12752122
2006 Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. The Journal of investigative dermatology 134 16601670
2022 Neutrophil Extracellular Traps (NETs) Promote Non-Small Cell Lung Cancer Metastasis by Suppressing lncRNA MIR503HG to Activate the NF-κB/NLRP3 Inflammasome Pathway. Frontiers in immunology 125 35707534
2023 Molecular Mechanisms of Neutrophil Extracellular Trap (NETs) Degradation. International journal of molecular sciences 119 36902325
2005 LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum. The Journal of investigative dermatology 116 15675955
2016 Social amoebae trap and kill bacteria by casting DNA nets. Nature communications 104 26927887
2019 Post-Translational Modifications in NETosis and NETs-Mediated Diseases. Biomolecules 99 31416265
2015 In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders. Neural plasticity 99 26839720
2018 Platelets, NETs and cancer. Thrombosis research 91 29703474
2004 SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases. The Journal of investigative dermatology 82 15304086
2019 Perineuronal Nets and Their Role in Synaptic Homeostasis. International journal of molecular sciences 79 31443560
2021 Neutrophil Extracellular Traps (NETs) in Severe SARS-CoV-2 Lung Disease. International journal of molecular sciences 77 34445556
2012 The 420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation: implications for atopic dermatitis. Human molecular genetics 77 22730493
2005 Inhibition of human kallikreins 5 and 7 by the serine protease inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI). Biological chemistry 76 16307483
2021 Significance of NETs Formation in COVID-19. Cells 75 33466589
2017 Understanding the Entanglement: Neutrophil Extracellular Traps (NETs) in Cystic Fibrosis. Frontiers in cellular and infection microbiology 72 28428948
2021 Neutrophil Extracellular Traps (NETs) in Cancer Metastasis. Cancers 71 34885240
2007 Correlation between SPINK5 gene mutations and clinical manifestations in Netherton syndrome patients. The Journal of investigative dermatology 71 17989726
2022 The Fatal Circle of NETs and NET-Associated DAMPs Contributing to Organ Dysfunction. Cells 66 35741047
2022 The potential roles of type I interferon activated neutrophils and neutrophil extracellular traps (NETs) in the pathogenesis of primary Sjögren's syndrome. Arthritis research & therapy 66 35854322
2011 Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis. The Journal of investigative dermatology 60 21697885
2016 NETs in cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 59 27614687
2023 Neutrophil extracellular traps (NETs) in cardiovascular diseases: From molecular mechanisms to therapeutic interventions. Kardiologia polska 58 38189504
2010 Ex-vivo gene therapy restores LEKTI activity and corrects the architecture of Netherton syndrome-derived skin grafts. Molecular therapy : the journal of the American Society of Gene Therapy 53 20877344
2020 NETs in APS: Current Knowledge and Future Perspectives. Current rheumatology reports 52 32845378
2009 Diverse functions of perineuronal nets. Acta neurobiologiae experimentalis 52 20048772
2024 Astrocytes require perineuronal nets to maintain synaptic homeostasis in mice. Nature neuroscience 51 39020018
2020 Detection, Visualization, and Quantification of Neutrophil Extracellular Traps (NETs) and NET Markers. Methods in molecular biology (Clifton, N.J.) 51 31729003
2012 Neutrophil extracellular traps (NETs) and infection-related vascular dysfunction. Blood reviews 50 23021640
2010 Imaging of NETs with PET radiopharmaceuticals. The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of... 49 20168283
2011 Distinct SPINK5 and IL-31 polymorphisms are associated with atopic eczema and non-atopic hand dermatitis in Taiwanese nursing population. Experimental dermatology 47 22017185
2022 Association between neutrophil extracellular traps (NETs) and thrombosis in antiphospholipid syndrome. Thrombosis research 46 35561448
2021 Staphylococcus aureus induces neutrophil extracellular traps (NETs) and neutralizes their bactericidal potential. Computational and structural biotechnology journal 45 34194670
2019 Aggregated NETs Sequester and Detoxify Extracellular Histones. Frontiers in immunology 45 31572386
2018 Relative antibacterial functions of complement and NETs: NETs trap and complement effectively kills bacteria. Molecular immunology 45 29571059
2011 Association of SPINK5 gene polymorphisms with atopic dermatitis in Northeast China. Journal of the European Academy of Dermatology and Venereology : JEADV 44 21585560
2002 LEKTI: a multidomain serine proteinase inhibitor with pathophysiological relevance. The international journal of biochemistry & cell biology 44 11943586
2022 Radiomics in pulmonary neuroendocrine tumours (NETs). La Radiologia medica 42 35538389
2023 Targeting NETs using dual-active DNase1 variants. Frontiers in immunology 41 37287977
2019 A novel tumor suppressor SPINK5 targets Wnt/β-catenin signaling pathway in esophageal cancer. Cancer medicine 41 30868765
2016 Caught in the Net: Perineuronal Nets and Addiction. Neural plasticity 41 26904301
2023 Identification of NETs-related biomarkers and molecular clusters in systemic lupus erythematosus. Frontiers in immunology 40 37143669
2016 Understanding the molecular mechanisms of NETs and their role in antiviral innate immunity. Virus research 40 27923601
2004 LEKTI demonstrable by immunohistochemistry of the skin: a potential diagnostic skin test for Netherton syndrome. The British journal of dermatology 39 15606522
2021 Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs). Comprehensive Physiology 38 33577121
2020 mTOR Pathway in Gastroenteropancreatic Neuroendocrine Tumor (GEP-NETs). Frontiers in endocrinology 38 33304317
2012 Colonic and rectal NET's. Best practice & research. Clinical gastroenterology 38 23582918
2022 Aging hampers neutrophil extracellular traps (NETs) efficacy. Aging clinical and experimental research 36 35920993
2021 Current treatments and future potential of surufatinib in neuroendocrine tumors (NETs). Therapeutic advances in medical oncology 36 34484432
2016 Incomplete KLK7 Secretion and Upregulated LEKTI Expression Underlie Hyperkeratotic Stratum Corneum in Atopic Dermatitis. The Journal of investigative dermatology 36 27769847
2004 Expression of LEKTI domains 6-9' in the baculovirus expression system: recombinant LEKTI domains 6-9' inhibit trypsin and subtilisin A. Protein expression and purification 35 15039071
2022 Role of Neutrophils and NETs in Animal Models of Thrombosis. International journal of molecular sciences 32 35163333
2025 Neutrophils and NETs in kidney disease. Nature reviews. Nephrology 31 40102634
2024 Low-Density Neutrophils and Neutrophil Extracellular Traps (NETs) Are New Inflammatory Players in Heart Failure. The Canadian journal of cardiology 31 38555028
2023 The Formation of NETs and Their Mechanism of Promoting Tumor Metastasis. Journal of oncology 31 36942262
2015 GEP-NETs update: Biotherapy for neuroendocrine tumours. European journal of endocrinology 31 25430657
2006 SPINK5, the defective gene in netherton syndrome, encodes multiple LEKTI isoforms derived from alternative pre-mRNA processing. The Journal of investigative dermatology 31 16374478
2024 TGF-β-driven LIF expression influences neutrophil extracellular traps (NETs) and contributes to peritoneal metastasis in gastric cancer. Cell death & disease 30 38490994
2024 S100A7 orchestrates neutrophil chemotaxis and drives neutrophil extracellular traps (NETs) formation to facilitate lymph node metastasis in cervical cancer patients. Cancer letters 30 39384116
2023 The involvement of NETs in ANCA-associated vasculitis. Frontiers in immunology 30 37781373
2014 Differentially instructive extracellular protein micro-nets. Journal of the American Chemical Society 29 24825365
2014 Gastrointestinal neuroendocrine tumors (NETs): new diagnostic and therapeutic challenges. Cancer metastasis reviews 28 24390486
2019 Compound K improves skin barrier function by increasing SPINK5 expression. Journal of ginseng research 27 33192123
2024 The Dual Role of Neutrophil Extracellular Traps (NETs) in Sepsis and Ischemia-Reperfusion Injury: Comparative Analysis across Murine Models. International journal of molecular sciences 26 38612596
2012 Knotting the NETs: analyzing histone modifications in neutrophil extracellular traps. Arthritis research & therapy 26 22524286
2002 The 15-domain serine proteinase inhibitor LEKTI: biochemical properties, genomic organization, and pathophysiological role. European journal of medical research 26 11891144
2024 Nets in fibrosis: Bridging innate immunity and tissue remodeling. International immunopharmacology 25 38906006
2022 Nets, pulmonary arterial hypertension, and thrombo-inflammation. Journal of molecular medicine (Berlin, Germany) 25 35441845
2016 NETs: organ-related epigenetic derangements and potential clinical applications. Oncotarget 25 27418145
2022 Metformin inhibits melanoma cell metastasis by suppressing the miR-5100/SPINK5/STAT3 axis. Cellular & molecular biology letters 24 35705923
2022 Correlation between Neutrophil Extracellular Traps (NETs) Expression and Primary Graft Dysfunction Following Human Lung Transplantation. Cells 24 36359815
2024 NETs: Important players in cancer progression and therapeutic resistance. Experimental cell research 23 39094902
2024 IL33-induced neutrophil extracellular traps (NETs) mediate a positive feedback loop for synovial inflammation and NET amplification in rheumatoid arthritis. Experimental & molecular medicine 23 39617790
2025 Neutrophil Extracellular Traps (NETs) in health and disease. Molecular biomedicine 22 41335221
2023 Who and how, DNA sensors in NETs-driven inflammation. Frontiers in immunology 22 37187738
2025 Unraveling NETs in Sepsis: From Cellular Mechanisms to Clinical Relevance. International journal of molecular sciences 21 40806591
2023 High-salt transcription from enzymatically gapped promoters nets higher yields and purity of transcribed RNAs. Nucleic acids research 20 36718937
2021 Sexually dimorphic perineuronal nets in the rodent and primate reproductive circuit. The Journal of comparative neurology 20 33950531
2010 rAAV2-mediated restoration of LEKTI in LEKTI-deficient cells from Netherton patients. Journal of dermatological science 20 21251800
2024 naRNA-LL37 composite DAMPs define sterile NETs as self-propagating drivers of inflammation. EMBO reports 19 38783164

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