ArticleJournal of proteomics2022
MMP-12 polarizes neutrophil signalome towards an apoptotic signature.
Article in Journal of proteomics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 19 citations in OpenAlex.
- Identification of distinct and shared biomarker panels in different manifestations of cerebral small-vessel disease through proteomic profiling.Nature aging · 2026Article
- Review
- Integrated machine learning and causal inference reveal CHRDL1 as a diagnostic and functional biomarker in NSCLC.Discover oncology · 2025Article
- Identification of distinct and shared biomarker panels in different manifestations of cerebral small vessel disease through proteomic profiling.medRxiv : the preprint server for health sciences · 2025Article
- Neutrophil extracellular traps: a novel contributor to vascular calcification in chronic kidney disease.Frontiers in immunology · 2025Article
- Manipulating host secreted protein gene expression: an indirect approach by HPV11/16 E6/E7 to suppress PBMC cytokine secretion.Virology journal · 2024Article
- The association between adipokines and pulmonary diseases: a mendelian randomization study.BMC pulmonary medicine · 2024Article
- Skin wound healing as a mirror to cardiac wound healing.Experimental physiology · 2023Review
- Diversity of cells and signals in the cardiovascular system.The Journal of physiology · 2023Article
- The cardiac wound healing response to myocardial infarction.WIREs mechanisms of disease · 2023Review
- FOXO1 regulates NLRP3 inflammasome proteins in LPS-induced cardiotoxicity.American journal of translational research · 2023Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
While macrophages are well-known to polarize across the inflammatory spectrum, neutrophils have only recently been found to activate in a similar fashion in response to pro- or anti-inflammatory stimuli. Matrix metalloproteinase (MMP)-12 mediates neutrophil physiology with direct signaling mechanisms yet to be investigated. We hypothesized MMP-12 may modify neutrophil signaling. Bone marrow neutrophils were stimulated with interleukin (IL-1β; pro-inflammatory), IL-4 (anti-inflammatory), or MMP-12. The secretome was mapped by multi-analyte profiling and intracellular signaling evaluated by array. IL-1β induced a cytokine-mediated inflammatory LPS-like signalome, with upregulation of pro-inflammatory cytokines such as interferon gamma (IFNγ,15.2-fold,p = 0.001), chemokine (C-X-C motif) ligand 1 (CXCL1,8.4-fold,p = 0.005), and tumor necrosis factor alpha (TNFα,11.2-fold,p = 0.004). IL-4 induced strong intracellular signaling with upregulation of mitogen-activated protein kinase kinase (MEK1;1.9-fold,p = 0.0005) and downregulation of signal transducer and activator of transcription 4 (STAT4;0.77-fold,0.001). MMP-12 increased IL-4 secretion 20-fold and induced a robust apoptotic neutrophil signalome with upregulation of forkhead box O1 (FOXO1;1.4-fold,p < 0.0001) and downregulation of WNT signaling with MMP-12 cleavage of the adherens junction components β-catenin, cahderin-3, and catenin-α2. In conclusion, neutrophils shifted phenotype by stimuli, with MMP-12 inducing a unique apoptotic signalome with higher resemblance to the anti-inflammatory signalome. SIGNIFICANCE: This study revealed that neutrophils demonstrate unique polarization signaling responses to specific stimuli, with the matrix metalloproteinase (MMP)-12 signalome showing similarity to the IL-4 signalome. MMP-12 polarized neutrophils towards a strong apoptotic signature by upregulating FOXO1 and downregulating WNT signaling. Our results highlight that neutrophils display more plasticity than previously appreciated.
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Registered trials
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