Affinage

ELANE

Neutrophil elastase · UniProt P08246

Length
267 aa
Mass
28.5 kDa
Annotated
2026-04-28
100 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELANE encodes neutrophil elastase (NE), a serine protease stored in primary granules that functions in innate immune defense, chromatin remodeling during myeloid differentiation, and regulation of cell death pathways. Transcription of ELANE is activated by LEF-1 and C/EBPα and repressed by GFI1 and miR-608, and its expression is tightly coupled to myeloid lineage commitment (PMID:12778173, PMID:19620402, PMID:31749032). Dominant heterozygous ELANE mutations cause cyclic neutropenia and severe congenital neutropenia through NE protein misfolding, mislocalization away from primary granules, ER stress/UPR activation, and promyelocyte death, with NMD-escaping truncated isoforms being the pathogenic species (PMID:10581030, PMID:21285438, PMID:26193632, PMID:33513358). Beyond granulopoiesis, NE catalyzes amino-terminal cleavage of histone H3 to regulate chromatin accessibility during monocyte-to-macrophage differentiation and promotes hepatocyte ferroptosis by stabilizing KEAP1 to suppress the NRF2–GPX4 antioxidant axis (PMID:34017121, PMID:40204709).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 Medium

    Characterization of the mouse Ela2 locus established the five-exon gene structure and identified conserved catalytic triad residues and proximal promoter elements (c-myb, ets), providing the foundation for understanding ELANE transcriptional regulation.

    Evidence FISH mapping, gene sequencing, and promoter element analysis in the mouse genome

    PMID:9925946

    Open questions at the time
    • Functional validation of c-myb and ets sites by mutagenesis not performed
    • Promoter element analysis based partly on homology
  2. 1999 High

    Positional cloning resolved the long-standing question of what causes cyclic neutropenia, identifying heterozygous ELANE mutations as the genetic basis of 21-day oscillatory hematopoiesis.

    Evidence Genome-wide linkage and sequencing of ELA2 in 13 independent families

    PMID:10581030

    Open questions at the time
    • Mechanism by which mutations perturb neutrophil production was unknown
    • Whether same gene underlies severe congenital neutropenia was untested
  3. 2003 High

    Two independent studies defined the transcriptional circuitry controlling ELANE: GFI1 was shown to directly repress ELANE (with GFI1 loss-of-function mutations causing neutropenia via de-repression), while LEF-1 and CBFα/RUNX1 were shown to co-activate the ELANE promoter, with SCN-associated promoter mutations disrupting LEF-1 binding.

    Evidence ChIP, EMSA, reporter assays, patient bone marrow transcript quantification, in vitro pull-down of LEF-1–CBFα interaction

    PMID:12778173 PMID:14594802

    Open questions at the time
    • How the balance of activating and repressing inputs is temporally regulated during granulopoiesis
    • Whether promoter mutations and coding mutations cause disease through the same downstream pathway
  4. 2007 Medium

    The pathogenic mechanism of ELANE mutations was resolved as multifactorial — mislocalization away from primary granules, impaired proteolytic activity, and UPR induction each contribute independently to disease, establishing misfolding/mistrafficking as a central pathogenic process.

    Evidence Biochemical activity assays, subcellular localization, and UPR reporter assays in patient cells with double de novo mutations

    PMID:17436313

    Open questions at the time
    • Relative contribution of each mechanism to clinical severity not quantified
    • Single-laboratory study with rare compound mutations
  5. 2009 High

    Functional rescue experiments demonstrated that LEF-1 is required for ELANE expression and neutrophil differentiation: LEF-1 knockdown reduced NE, while LEF-1 re-expression in SCN patient CD34+ cells restored granulopoiesis.

    Evidence shRNA knockdown and lentiviral LEF-1 rescue of patient CD34+ cells with differentiation readout

    PMID:19620402

    Open questions at the time
    • Whether LEF-1 acts solely through ELANE or also regulates other granulopoietic targets
  6. 2011 High

    A transgenic mouse model with the G193X Elane mutation provided in vivo proof that UPR/ER stress drives neutropenia: granulocytic precursors were selectively vulnerable to ER stress, and proteasome inhibition blocking ERAD caused marked neutropenia, while Perk knockout provided genetic epistasis.

    Evidence Transgenic mouse model, chemical ER stress, PERK KO epistasis, proteasome inhibitor treatment

    PMID:21285438

    Open questions at the time
    • Whether all ELANE mutation classes operate through UPR or whether some act via gain-of-toxic-function
    • Why granulocytic precursors are selectively sensitive to UPR compared to other lineages
  7. 2013 High

    Discovery that ELANE start-codon mutations produce truncated NE isoforms via an internal IRES explained how loss of the normal initiation codon generates toxic proteins rather than null alleles, reducing myeloid clonogenic capacity.

    Evidence Patient iPSC differentiation, IRES deletion/mutagenesis, in vitro colony formation assay

    PMID:24184683

    Open questions at the time
    • Whether IRES-driven truncated isoforms misfold or have aberrant enzymatic activity
    • Structural characterization of truncated isoforms not performed
  8. 2015 High

    Pharmacological rescue with sivelestat (NE-specific inhibitor) demonstrated that NE enzymatic activity and/or mislocalization directly cause the promyelocyte death and differentiation arrest, as sivelestat corrected NE localization, ameliorated UPR, restored C/EBPα expression, and rescued dysgranulopoiesis in patient iPSCs.

    Evidence SCN patient iPSC genome editing/differentiation, NE localization imaging, UPR assays, sivelestat treatment

    PMID:26193632

    Open questions at the time
    • Whether sivelestat acts by inhibiting enzymatic activity or by chaperoning NE folding
    • Clinical translatability of sivelestat to SCN patients
  9. 2017 Medium

    Beta-lactam NE inhibitors and an ELANE mutation affecting NETosis extended the therapeutic and functional framework: MK0339 rescued myeloid progenitor survival, while a novel mutation demonstrated that ELANE is required for normal NET formation and neutrophil activation.

    Evidence Patient iPSC and HL60 pharmacological rescue (MK0339); patient neutrophil NET assays and elastase activity measurement

    PMID:28754797 PMID:28881492

    Open questions at the time
    • Direct structural evidence for chaperone mechanism of beta-lactam inhibitors lacking
    • Whether defective NETosis is a general feature of ELANE mutations or specific to certain alleles
  10. 2019 Medium

    miR-608 was identified as a post-transcriptional regulator of ELANE in monocytes, directly targeting the ELANE 3′UTR to repress expression, adding a new layer of regulation beyond transcription factor control.

    Evidence Lentiviral miR-608 inhibition in U937 cells, luciferase reporter with seed-sequence mutagenesis

    PMID:31749032

    Open questions at the time
    • Physiological relevance of miR-608 regulation in primary granulocytes not demonstrated
    • Whether miR-608 dysregulation contributes to neutropenia
  11. 2021 High

    Three 2021 studies resolved distinct questions: (1) a CRISPR screen in HSPCs demonstrated that NMD-escaping late-exon frameshifts are the pathogenic ELANE alleles, while early-exon NMD-triggering frameshifts support normal neutrophil maturation; (2) NE was shown to catalyze histone H3 amino-terminal cleavage in monocytes, regulating chromatin accessibility during differentiation; (3) ELANE-mutant iPSC progenitors displayed elevated ROS and PML nuclear bodies in a feed-forward loop with ELANE expression.

    Evidence Pooled CRISPR screen in HSPCs with xenotransplantation; siRNA depletion with ATAC-seq in monocytes; iPSC hematopoietic progenitors with PML deletion and ELANE correction

    PMID:33513358 PMID:33560392 PMID:34017121

    Open questions at the time
    • Whether histone H3 cleavage by NE occurs in granulocytic precursors or is monocyte-specific
    • How PML nuclear body formation feeds back to regulate ELANE expression mechanistically
    • Whether the NMD-escape model fully explains all SCN-causing ELANE missense mutations
  12. 2025 Medium

    A non-hematopoietic role for NE was established: ELANE promotes hepatocyte ferroptosis in metabolic liver disease by disrupting the P62–KEAP1 interaction, stabilizing KEAP1, enhancing NRF2 ubiquitination and degradation, and reducing GPX4-mediated antioxidant defense.

    Evidence Elane-KO mice on HFD, primary hepatocyte MAFLD model, recombinant ELANE treatment, Co-IP for ELANE/KEAP1/P62 interactions, ubiquitination assays

    PMID:40204709

    Open questions at the time
    • Source of ELANE in hepatocyte microenvironment (neutrophil-derived vs. hepatocyte-intrinsic) not fully delineated
    • Whether this KEAP1-stabilizing activity is relevant in other tissues
    • Single laboratory finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: why granulocytic precursors are selectively vulnerable to ELANE-induced UPR compared to other hematopoietic lineages; the structural basis of how specific mutations cause misfolding versus aberrant enzymatic activity; and the full physiological scope of NE's chromatin-remodeling and ferroptosis-promoting activities outside neutrophils.
  • No crystal structure of disease-causing NE mutants
  • Lineage-selective UPR sensitivity mechanism unknown
  • In vivo validation of histone H3 cleavage function in granulopoiesis lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0140096 catalytic activity, acting on a protein 2 GO:0042393 histone binding 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-4839726 Chromatin organization 1
Partners
CBFA2T3GFI1KEAP1LEF1NFE2L2SQSTM1

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Heterozygous single-base substitutions in ELA2 (encoding neutrophil elastase, a serine protease of neutrophil and monocyte granules) cause cyclic haematopoiesis, mapping to chromosome 19p13.3; mutations were identified on unique haplotypes in 13/13 families, establishing ELA2 mutations as the genetic cause of 21-day oscillatory haematopoiesis, hypothesized to perturb elastase-serpin interactions. Genome-wide linkage screen, positional cloning, direct sequencing of ELA2 in affected families Nature genetics High 10581030
2003 GFI1, a transcriptional repressor, directly represses ELA2 transcription; dominant-negative GFI1 zinc-finger mutations cause neutropenia by de-repressing ELA2, linking the two genes in a common myeloid differentiation pathway. Chromatin immunoprecipitation, electrophoretic mobility shift assay, reporter assays, in vivo ELA2 expression measurement in neutropenic patients Nature genetics High 12778173
2003 LEF-1 and CBFα (AML1/RUNX1) co-activate the human ELA2 promoter; LEF-1 high-mobility-group domain physically interacts with the runt DNA-binding and PST activation domains of CBFα; ELA2 promoter substitutions in SCN patients disrupt a LEF-1 motif adjacent to the CBFα site, elevating ELA2 transcription in bone marrow. Reporter assay, in vitro pull-down/protein interaction assay, patient bone marrow ELA2 transcript quantification The Journal of biological chemistry High 14594802
2007 ELANE mutations impair neutrophil elastase subcellular trafficking (mislocalization away from primary granules) and induce the unfolded protein response (UPR); analysis of double de novo mutations showed that effects on proteolytic activity, subcellular localization, and UPR induction each contribute independently and somewhat additively to disease pathogenesis, supporting mistrafficking as a disease mechanism. Biochemical characterization of proteolytic activity, subcellular localization assays, UPR reporter assays in patient-derived cells carrying defined mutations Human mutation Medium 17436313
2009 LEF-1 and C/EBPα directly bind the ELA2 promoter and activate ELANE transcription; shRNA knockdown of LEF-1 markedly reduces ELA2/NE levels in hematopoietic cells, and LEF-1 rescue of CD34+ cells from congenital neutropenia patients restores granulocytic differentiation with increased functionally active NE. Promoter binding assay (direct binding), shRNA knockdown, lentiviral LEF-1 rescue of patient CD34+ cells with functional differentiation readout Blood High 19620402
2011 ELANE mutations cause SCN through a UPR/ER stress mechanism: transgenic mice expressing the G193X Elane allele (producing truncated NE rapidly degraded by ERAD) show selective sensitivity of granulocytic precursors to ER stress; proteasome inhibition blocking ERAD causes marked neutropenia, providing strong support for the UPR model. Transgenic mouse model with targeted Elane mutation, chemical ER stress induction, PERK knockout epistasis, proteasome inhibitor treatment with neutrophil count readout Blood High 21285438
2013 ELANE mutations that disrupt the translational start site force translation from downstream in-frame initiation codons, producing amino-terminally truncated NE isoforms lacking pre- and pro-sequences but retaining catalytic residues; an internal ribosome entry site (IRES) within ELANE mediates this alternative translation; expression of truncated isoforms reduces myeloid clonogenic capacity. Patient iPSC differentiation, IRES deletion/mutation analysis, in vitro expression of truncated isoforms with colony formation assay Blood High 24184683
2015 ELANE point mutations cause promyelocyte death and differentiation arrest via NE mislocalization (away from primary granules) and activation of UPR/ER stress; sivelestat (NE-specific inhibitor) corrects dysgranulopoiesis by restoring normal intracellular NE localization, ameliorating UPR, increasing C/EBPα expression, and promoting promyelocyte survival in SCN patient-derived iPSCs. SCN patient iPSC generation/genome editing/differentiation, NE localization imaging, UPR assays, CEBPA/CEBPB expression analysis, sivelestat pharmacological rescue The Journal of clinical investigation High 26193632
2021 ELANE-encoded neutrophil elastase (NE) catalyzes proteolytic cleavage of histone H3 at the amino terminus (H3ΔN) in monocytes; this mark is distributed across permissive chromatin and actively transcribed genes; NSP (including NE) repression during monocyte-to-macrophage differentiation reduces H3ΔN, increasing chromatin accessibility and priming gene expression reprogramming. Simultaneous siRNA depletion of cathepsin G, neutrophil elastase, and proteinase 3 in monocytic cells; ATAC-seq; integrative epigenomic analysis; primary monocyte and macrophage comparisons Nature immunology High 34017121
2021 SCN patient-derived iPSC hematopoietic progenitors with ELANE misfolding mutations display elevated ROS and increased PML nuclear bodies (marker of acute oxidative stress); PML controls both metabolic state and ELANE expression in a feed-forward mechanism; PML deletion or ELANE mutation correction restores normal CSF3 (G-CSF) responses. iPSC-derived hematopoietic progenitors from SCN patients, ROS measurement, PML nuclear body quantification, PML deletion, ELANE mutation correction, CSF3 response assay Blood advances Medium 33560392
2021 CRISPR pooled screen in human HSPCs established that ELANE early-exon frameshift alleles (causing NMD) support neutrophil maturation, whereas terminal exon frameshift alleles that escape NMD recapitulate neutrophil maturation arrest; specifically only -1 frame late-exon indels impede maturation, while -2 frame late-exon indels suppress translation and support maturation, defining NMD escape as the pathogenic mechanism. Pooled CRISPR screen in human HSPCs, allele-specific editing, NMD analysis, xenotransplantation engraftment assay, in vitro neutrophil differentiation Cell stem cell High 33513358
2017 Beta-lactam-based NE inhibitors (particularly MK0339), acting as enzymatic inhibitors or chaperones for mutant NE, promote survival of myeloid progenitors and increase mature neutrophil formation in ELANE-mutant cells, suggesting that direct inhibition of NE enzymatic activity or correction of protein misfolding can rescue differentiation. Patient iPSCs, HL60 cells with transient or regulated mutant NE expression, annexin V/FACS survival assay, neutrophil formation assay with NE inhibitor treatment Journal of leukocyte biology Medium 28754797
2017 A novel ELANE mutation causes defective NETosis: patient neutrophils show significantly decreased NET formation, reduced neutrophil activation, and reduced elastase activity; 3D modeling suggests the mutation alters protein folding and surface charge distribution, potentially disrupting protein trafficking. Scanning electron microscopy of NETs, flow cytometry for neutrophil activation, fluorescent substrate-based elastase activity assay, PyMOL 3D protein modeling Arthritis & rheumatology (Hoboken, N.J.) Medium 28881492
2019 miR-608 post-transcriptionally regulates ELANE expression in human monocytes; inhibition of miR-608 upregulates ELANE mRNA and protein; luciferase reporter assay confirmed direct miR-608 targeting of the ELANE 3'UTR, and mutation of the seed sequence abolished repression. Lentiviral miR-608 inhibition in U937 cells, cDNA microarray, luciferase reporter cotransfection with miR-608 mimic and seed-sequence mutant Journal of clinical immunology Medium 31749032
1998 Mouse Ela2 (neutrophil elastase) and Prtn3 (proteinase 3) genes share a common location on mouse chromosome 10C2 and are within 2.2 kb of each other; each gene has five exons and four introns; the catalytic triad residues and their placement are conserved; the proximal Ela2 promoter contains functional c-myb and ets transcriptional elements. FISH chromosomal localization, gene structure characterization by sequencing, promoter element identification Cytogenetics and cell genetics Medium 9925946
2025 ELANE (neutrophil elastase) promotes hepatocyte ferroptosis in MAFLD by enhancing KEAP1 protein stability: ELANE weakens the binding between P62 and KEAP1, inhibiting lysosomal degradation of KEAP1, thereby increasing KEAP1 levels, enhancing ubiquitination and degradation of NRF2, and reducing GPX4 expression, leading to lipid ROS accumulation and ferroptosis. Elane-KO mice with HFD model, primary hepatocyte FFA-induced MAFLD model, recombinant ELANE treatment, Co-IP (ELANE/KEAP1/P62 interaction), ubiquitination assay, Western blotting for NRF2/GPX4/KEAP1 Cell death & disease Medium 40204709
2022 ELANE promotes M2 macrophage polarization by downregulating PTEN expression, which in turn promotes lung cancer cell proliferation, migration, and invasion in vitro and tumor growth in vivo. THP-1 monocyte-to-M2 macrophage differentiation assay, flow cytometry for CD206+ macrophages, Western blotting for PTEN, conditioned medium co-culture with lung cancer cell lines (A549, H1299), in vivo xenograft Immunological investigations Low 36102787

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell death and differentiation 479 24096871
2014 Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox biology 401 25598486
1999 Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nature genetics 335 10581030
2003 Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nature genetics 290 12778173
2006 Protein adducts generated from products of lipid oxidation: focus on HNE and one. Drug metabolism reviews 278 17145694
1989 Two epithelial tumor cell lines (HNE-1 and HONE-1) latently infected with Epstein-Barr virus that were derived from nasopharyngeal carcinomas. Proceedings of the National Academy of Sciences of the United States of America 204 2556716
2016 Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders. Free radical biology & medicine 200 27789292
2016 4-Hydroxynonenal (HNE) modified proteins in metabolic diseases. Free radical biology & medicine 185 27815191
2017 Pathophysiology of mitochondrial lipid oxidation: Role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in mitochondria. Free radical biology & medicine 173 28456642
2003 The proteasomal system and HNE-modified proteins. Molecular aspects of medicine 160 12892997
2022 Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases. Journal of immunology research 155 35411309
2016 Antioxidants and HNE in redox homeostasis. Free radical biology & medicine 149 27888001
2004 Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood 145 14962902
2004 Mass spectrometry for detection of 4-hydroxy-trans-2-nonenal (HNE) adducts with peptides and proteins. Mass spectrometry reviews 140 15133838
2009 Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. British journal of haematology 129 19775295
2010 Trans-4-hydroxy-2-hexenal, a product of n-3 fatty acid peroxidation: make some room HNE.. Free radical biology & medicine 124 20353821
2015 The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Current opinion in hematology 122 25427142
2006 Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE): role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth. The Journal of biological chemistry 122 16648138
1998 Inhibition of cytochrome c oxidase activity by 4-hydroxynonenal (HNE). Role of HNE adduct formation with the enzyme subunits. Biochimica et biophysica acta 119 9555085
2017 Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds. Free radical biology & medicine 111 28192230
2001 Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease. Blood 103 11675333
2008 Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. British journal of haematology 101 19120359
2001 Overexpression of mitochondrial manganese superoxide dismutase protects against radiation-induced cell death in the human hepatocellular carcinoma cell line HLE. Cancer research 97 11454680
2013 Measurement of HNE-protein adducts in human plasma and serum by ELISA-Comparison of two primary antibodies. Redox biology 92 24024156
1993 NE-100, a novel sigma receptor ligand: in vivo tests. Life sciences 91 7901723
2012 ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematology/oncology clinics of North America 79 23351986
2019 Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling. Cell death and differentiation 77 31819159
2011 Control of protein function by reversible Nɛ-lysine acetylation in bacteria. Current opinion in microbiology 77 21239213
2016 Contribution of the HNE-immunohistochemistry to modern pathological concepts of major human diseases. Free radical biology & medicine 73 27993730
2013 The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Human mutation 73 23463630
2009 Contaminant accumulation and multi-biomarker responses in field collected zebra mussels (Dreissena polymorpha) and crayfish (Procambarus clarkii), to evaluate toxicological effects of industrial hazardous dumps in the Ebro river (NE Spain). Chemosphere 72 19954812
2011 Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane. Blood 69 21285438
2024 Monitoring norepinephrine release in vivo using next-generation GRABNE sensors. Neuron 68 38547869
1995 Molecular cloning and functional expression of bacteriophage PK1E-encoded endoneuraminidase Endo NE. Molecular microbiology 68 7565105
2020 SARS-CoV-2 RNA detection and persistence in wastewater samples: An experimental network for COVID-19 environmental surveillance in Padua, Veneto Region (NE Italy). The Science of the total environment 64 33187717
1999 Formation and export of the glutathione conjugate of 4-hydroxy-2, 3-E-nonenal (4-HNE) in hepatoma cells. Archives of biochemistry and biophysics 63 9882435
2015 Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells. The Journal of clinical investigation 61 26193632
2015 Establishment of NE asymmetry—targeting of membrane proteins to the inner nuclear membrane. Current opinion in cell biology 59 26112002
2022 What Is Ne, Anyway? The Journal of heredity 57 35532202
2011 Mutations in the ELANE gene are associated with development of periodontitis in patients with severe congenital neutropenia. Journal of clinical immunology 57 21796505
2007 The lipid peroxidation end-product 4-HNE induces COX-2 expression through p38MAPK activation in 3T3-L1 adipose cell. FEBS letters 57 17481611
2021 Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation. Nature immunology 56 34017121
2003 Genotoxicity of HNE. Molecular aspects of medicine 50 12892993
2003 Proteome analysis of lens epithelia, fibers, and the HLE B-3 cell line. Investigative ophthalmology & visual science 50 14578405
2006 Regulation of CD95 (Fas) expression and Fas-mediated apoptotic signaling in HLE B-3 cells by 4-hydroxynonenal. Biochemistry 48 17014078
2007 Glutathione level regulates HNE-induced genotoxicity in human erythroleukemia cells. Toxicology and applied pharmacology 45 18096195
2001 Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia. British journal of haematology 45 11722436
2020 Variability in genes related to SARS-CoV-2 entry into host cells (ACE2, TMPRSS2, TMPRSS11A, ELANE, and CTSL) and its potential use in association studies. Life sciences 44 32835700
2021 Dissecting ELANE neutropenia pathogenicity by human HSC gene editing. Cell stem cell 43 33513358
2017 "Canary Islands (NE Atlantic) as a biodiversity 'hotspot' of Gambierdiscus: Implications for future trends of ciguatera in the area". Harmful algae 42 28755716
2002 The combined use of chemical and biochemical markers to assess water quality in two low-stream rivers (NE Spain). Environmental research 42 12483808
2017 HNE as an inducer of COX-2. Free radical biology & medicine 41 28192229
2007 Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells. Molecular cancer therapeutics 39 18025272
2017 HNE and cholesterol oxidation products in colorectal inflammation and carcinogenesis. Free radical biology & medicine 37 28089726
2013 Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms. Blood 37 24184683
2006 Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations. The Journal of pediatrics 37 16737875
2020 CRISPR-Cas9-Mediated ELANE Mutation Correction in Hematopoietic Stem and Progenitor Cells to Treat Severe Congenital Neutropenia. Molecular therapy : the journal of the American Society of Gene Therapy 35 32822592
2016 Pro-apoptotic effects of lipid oxidation products: HNE at the crossroads of NF-κB pathway and anti-apoptotic Bcl-2. Free radical biology & medicine 35 27840321
2009 Effects of HNE-modification induced by Abeta on neprilysin expression and activity in SH-SY5Y cells. Journal of neurochemistry 34 19196432
2003 Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2. The Journal of biological chemistry 33 14594802
2020 How Much Does N Vary Among Species? Genetics 28 32839240
2017 Elastase inhibitors as potential therapies for ELANE-associated neutropenia. Journal of leukocyte biology 28 28754797
2009 Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1. Blood 28 19620402
2021 An Update on Ciguatoxins and CTX-like Toxicity in Fish from Different Trophic Levels of the Selvagens Islands (NE Atlantic, Madeira, Portugal). Toxins 27 34437451
2007 Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia. Human mutation 27 17436313
2023 Relationship between 4-Hydroxynonenal (4-HNE) as Systemic Biomarker of Lipid Peroxidation and Metabolomic Profiling of Patients with Prostate Cancer. Biomolecules 26 36671530
2014 Is Lys-Nɛ-acetylation the next big thing in post-translational modifications? Trends in plant science 26 24866592
2008 alpha-Tocopherol, MDA-HNE and 8-OHdG levels in liver and heart mitochondria of adriamycin-treated rats fed with alcohol-free beer. Toxicology 24 18513847
2007 Hypothalamic and hindbrain NPY, AGRP and NE increase consummatory feeding responses. Physiology & behavior 24 17289093
1999 Inhibitory role of plasminogen activator inhibitor-1 in invasion and proliferation of HLE hepatocellular carcinoma cells. Japanese journal of cancer research : Gann 23 10470287
2004 Arctic atmospheric contaminants in NE Greenland: levels, variations, origins, transport, transformations and trends 1990-2001. The Science of the total environment 22 15325139
2005 In vitro modification of solid phase multiple antigenic peptides/autoantigens with 4-hydroxy-2-nonenal (HNE) provide ideal substrates for detection of anti-HNE antibodies and peptide antioxidants. Journal of immunological methods 21 16055145
2021 A possible pathogenic correlation between neutrophil elastase (NE) enzyme and inflammation in the pathogenesis of coronavirus disease 2019 (COVID-19). International immunopharmacology 20 34536744
2018 Using Pupillometry to Assess the Atypical Pupillary Light Reflex and LC-NE System in ASD. Behavioral sciences (Basel, Switzerland) 20 30469373
2023 Interrelationship of lipid aldehydes (MDA, 4-HNE, and 4-ONE) mediated protein oxidation in muscle foods. Critical reviews in food science and nutrition 19 37589270
2021 Inflammatory signature in acute-on-chronic liver failure includes increased expression of granulocyte genes ELANE, MPO and CD177. Scientific reports 19 34552111
2016 Immunochemical studies on HNE-modified HSA: Anti-HNE-HSA antibodies as a probe for HNE damaged albumin in SLE. International journal of biological macromolecules 19 26800898
2007 Degradation of HNE-modified proteins--possible role of ubiquitin. Redox report : communications in free radical research 19 17263912
2005 HNE-dependent molecular damage in diabetic nephropathy and its possible prevention by N-acetyl-cysteine and oxerutin. BioFactors (Oxford, England) 19 16403990
2020 The Appearance of 4-Hydroxy-2-Nonenal (HNE) in Squamous Cell Carcinoma of the Oropharynx. Molecules (Basel, Switzerland) 18 32079077
2017 Brief Report: A Novel ELANE Mutation Associated With Inflammatory Arthritis, Defective NETosis, and Recurrent Parvovirus Infection. Arthritis & rheumatology (Hoboken, N.J.) 18 28881492
2015 Clinical characteristics of severe congenital neutropenia caused by novel ELANE gene mutations. The Pediatric infectious disease journal 16 25162927
2021 He-Ne laser accelerates seed germination by modulating growth hormones and reprogramming metabolism in brinjal. Scientific reports 15 33846419
2014 Spionidae (Polychaeta: Canalipalpata: Spionida) from seamounts in the NE Atlantic. Zootaxa 15 24869536
2009 First report of Mycoplasma conjunctivae from wild Caprinae with infectious keratoconjunctivitis in the Pyrenees (NE Spain). Journal of wildlife diseases 15 19204357
2021 PML-controlled responses in severe congenital neutropenia with ELANE-misfolding mutations. Blood advances 14 33560392
2021 Immunohistopathological response against anisakid nematode larvae and a coccidian in Micromesistius poutassou from NE Atlantic waters. Journal of helminthology 14 33750484
2014 Effect of Nɛ-carboxymethyllysine on oxidative stress and the glutathione system in beta cells. Toxicology reports 14 28962310
2010 Are native naiads more tolerant to pollution than exotic freshwater bivalve species? An hypothesis tested using physiological responses of three species transplanted to mercury contaminated sites in the Ebro River (NE, Spain). Chemosphere 14 20952043
1998 Characterization and localization of the genes for mouse proteinase-3 (Prtn3) and neutrophil elastase (Ela2). Cytogenetics and cell genetics 14 9925946
1991 Rat brain metabolism enzyme activity variations following He-Ne laser irradiation. Molecular and chemical neuropathology 14 1776992
2025 ELANE enhances KEAP1 protein stability and reduces NRF2-mediated ferroptosis inhibition in metabolic dysfunction-associated fatty liver disease. Cell death & disease 13 40204709
2022 ELANE Promotes M2 Macrophage Polarization by Down-Regulating PTEN and Participates in the Lung Cancer Progression. Immunological investigations 13 36102787
2020 High Light Induced Alka(e)ne Biodegradation for Lipid and Redox Homeostasis in Cyanobacteria. Frontiers in microbiology 13 32765469
2019 MiR-608 Exerts Anti-inflammatory Effects by Targeting ELANE in Monocytes. Journal of clinical immunology 13 31749032
2016 4-HNE expression in diabetic rat kidneys and the protective effects of probucol. Journal of endocrinological investigation 13 26830905
2003 CYP2E1 overexpression up-regulates both non-specific delta-aminolevulinate synthase and heme oxygenase-1 in the human hepatoma cell line HLE/2E1. International journal of molecular medicine 13 12469218
2024 CRISPR-Cas9n-mediated ELANE promoter editing for gene therapy of severe congenital neutropenia. Molecular therapy : the journal of the American Society of Gene Therapy 12 38556793
2022 Characterization of an Anti-CD70 Half-Life Extended Bispecific T-Cell Engager (HLE-BiTE) and Associated On-Target Toxicity in Cynomolgus Monkeys. Toxicological sciences : an official journal of the Society of Toxicology 12 35583313
2021 Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice. Biomolecules 12 34944441