{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:58:56Z","timestamp":1790308736490,"version":"4.1.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":24,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI168210"],"award-info":[{"award-number":["R01AI168210"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>SERPINB1, a member of the serpin superfamily, functions primarily as a serine protease suicide inhibitor via its reactive center loop (RCL). While murine studies have elucidated its role in neutrophil homeostasis and survival, the functions and pathways orchestrated by human SERPINB1, particularly in monocytes, remain largely undefined. Here, we demonstrate that SERPINB1 is under purifying selection, indicative of an essential, non-redundant role in human immunity comparable to that of genes known to cause immune diseases when mutated. Flow cytometric and Western blot analyses reveal ubiquitous expression in immune cells, with monocytes exhibiting the highest levels and the most active utilization of SERPINB1. Using CRISPR\/Cas9-mediated knockout in THP-1 monocytic cells, we found that SERPINB1 deficiency does not impair cell viability but significantly enhances proinflammatory responses, notably increasing IL-1\u03b2 production in response to lipopolysaccharide stimulation. Bulk RNA sequencing corroborated upregulation of inflammatory genes, while activity-based proteomic profiling uncovered broad alterations in enzymatic activity, affecting pathways beyond protease regulation, including ribosomal function and cellular metabolism. These findings suggest that human SERPINB1 extends its function beyond protease inhibition to modulate monocyte inflammatory activation and metabolic processes. Further mechanistic investigations are warranted to delineate the molecular interactions underpinning SERPINB1\u2019s regulatory network in monocytes. Yet, our study provides novel insights into SERPINB1\u2019s multifaceted functions in human immunity and highlights its potential as a therapeutic target for controlling dysregulated inflammation.<\/jats:p>","DOI":"10.1093\/immhor\/vlag053","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:16:13Z","timestamp":1790306173000},"source":"Crossref","is-referenced-by-count":0,"title":["SERPINB1 as a critical regulator of inflammation and protease activity in human monocytic cells"],"prefix":"10.1093","volume":"10","author":[{"given":"Jareb J","family":"P\u00e9rez-Caraballo","sequence":"first","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Ye","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Cui","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7925-449X","authenticated-orcid":false,"given":"Rub\u00e9n","family":"Mart\u00ednez-Barricarte","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]},{"name":"Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]},{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]},{"name":"Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"2026092423160528300_vlag053-B1","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/s0378-1119(98)00189-9","article-title":"Structure and sequence of human M\/NEI (monocyte\/neutrophil elastase inhibitor), an Ov-serpin family gene","volume":"213","author":"Zeng","year":"1998","journal-title":"Gene"},{"key":"2026092423160528300_vlag053-B2","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1007\/s00018-003-3240-3","article-title":"Human clade B serpins (ov-serpins) belong to a cohort of evolutionarily dispersed intracellular proteinase inhibitor clades that protect cells from promiscuous proteolysis","volume":"61","author":"Silverman","year":"2004","journal-title":"Cell Mol Life Sci"},{"key":"2026092423160528300_vlag053-B3","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1186\/1471-2164-6-167","article-title":"Analysis of vertebrate genomes suggests a new model for clade B serpin evolution","volume":"6","author":"Kaiserman","year":"2005","journal-title":"BMC Genomics"},{"key":"2026092423160528300_vlag053-B4","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1073\/pnas.89.12.5635","article-title":"Sequence and molecular characterization of human monocyte\/neutrophil elastase inhibitor","volume":"89","author":"Remold-O\u2019Donnell","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026092423160528300_vlag053-B5","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.semcdb.2016.07.010","article-title":"The hidden side of SERPINB1\/Leukocyte elastase inhibitor","volume":"62","author":"Torriglia","year":"2017","journal-title":"Semin Cell Dev Biol"},{"key":"2026092423160528300_vlag053-B6","doi-asserted-by":"publisher","first-page":"15762","DOI":"10.1021\/bi0113925","article-title":"The serpin MNEI inhibits elastase-like and chymotrypsin-like serine proteases through efficient reactions at two active sites","volume":"40","author":"Cooley","year":"2001","journal-title":"Biochemistry"},{"key":"2026092423160528300_vlag053-B7","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1038\/s41590-018-0303-z","article-title":"SERPINB1-mediated checkpoint of inflammatory caspase activation","volume":"20","author":"Choi","year":"2019","journal-title":"Nat Immunol"},{"key":"2026092423160528300_vlag053-B8","doi-asserted-by":"publisher","first-page":"42028","DOI":"10.1074\/jbc.M207080200","article-title":"Characterization of four murine homologs of the human ov-serpin monocyte neutrophil elastase inhibitor MNEI (SERPINB1)","volume":"277","author":"Benarafa","year":"2002","journal-title":"J Biol Chem"},{"key":"2026092423160528300_vlag053-B9","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/B978-0-12-386471-0.00007-9","article-title":"The SerpinB1 knockout mouse a model for studying neutrophil protease regulation in homeostasis and inflammation","volume":"499","author":"Benarafa","year":"2011","journal-title":"Methods Enzymol"},{"key":"2026092423160528300_vlag053-B10","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1189\/jlb.0810461","article-title":"SerpinB1 protects the mature neutrophil reserve in the bone marrow","volume":"90","author":"Benarafa","year":"2011","journal-title":"J Leukoc Biol"},{"key":"2026092423160528300_vlag053-B11","doi-asserted-by":"publisher","first-page":"3900","DOI":"10.1182\/blood-2012-09-455022","article-title":"SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G","volume":"121","author":"Baumann","year":"2013","journal-title":"Blood"},{"key":"2026092423160528300_vlag053-B12","doi-asserted-by":"publisher","first-page":"4445","DOI":"10.1172\/JCI76246","article-title":"Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation","volume":"124","author":"Loison","year":"2014","journal-title":"J Clin Invest"},{"key":"2026092423160528300_vlag053-B13","doi-asserted-by":"publisher","first-page":"e2001248118","DOI":"10.1073\/pnas.2001248118","article-title":"Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance","volume":"118","author":"Rapaport","year":"2021","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2026092423160528300_vlag053-B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002806","article-title":"SnIPRE: selection inference using a Poisson random effects model","volume":"8","author":"Eilertson","year":"2012","journal-title":"PLoS Comput Biol"},{"key":"2026092423160528300_vlag053-B15","doi-asserted-by":"publisher","first-page":"26581","DOI":"10.1074\/jbc.M312481200","article-title":"Discordant regulation of granzyme H and granzyme B expression in human lymphocytes","volume":"279","author":"Sedelies","year":"2004","journal-title":"J Biol Chem"},{"key":"2026092423160528300_vlag053-B16","doi-asserted-by":"publisher","first-page":"20635","DOI":"10.1073\/pnas.1905762116","article-title":"SerpinB1 controls encephalitogenic T helper cells in neuroinflammation","volume":"116","author":"Hou","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026092423160528300_vlag053-B17","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abb1662","article-title":"Human inborn errors of immunity: an expanding universe","volume":"5","author":"Notarangelo","year":"2020","journal-title":"Sci Immunol"},{"key":"2026092423160528300_vlag053-B18","doi-asserted-by":"publisher","first-page":"e20250003","DOI":"10.70962\/jhi.20250003","article-title":"Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee","volume":"1","author":"Poli","year":"2025","journal-title":"J Hum Immun"},{"key":"2026092423160528300_vlag053-B19","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.ajhg.2015.11.014","article-title":"Genomic signatures of selective pressures and introgression from Archaic Hominins at Human Innate Immunity Genes","volume":"98","author":"Deschamps","year":"2016","journal-title":"Am J Hum Genet"},{"key":"2026092423160528300_vlag053-B20","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/nri3421","article-title":"Population genetic tools for dissecting innate immunity in humans","volume":"13","author":"Quintana-Murci","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"2026092423160528300_vlag053-B21","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.intimp.2014.08.002","article-title":"THP-1 cell line: an in vitro cell model for immune modulation approach","volume":"23","author":"Chanput","year":"2014","journal-title":"Int Immunopharmacol"},{"key":"2026092423160528300_vlag053-B22","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1084\/jem.20070494","article-title":"The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection","volume":"204","author":"Benarafa","year":"2007","journal-title":"J Exp Med"},{"key":"2026092423160528300_vlag053-B23","doi-asserted-by":"publisher","first-page":"100164","DOI":"10.1016\/j.crphar.2023.100164","article-title":"Activity-based protein profiling: a graphical review","volume":"5","author":"Porta","year":"2023","journal-title":"Curr Res Pharmacol Drug Discov"},{"key":"2026092423160528300_vlag053-B24","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1084\/jem.162.6.2142","article-title":"A fast-acting elastase inhibitor in human monocytes","volume":"162","author":"Remold-O\u2019Donnell","year":"1985","journal-title":"J Exp Med"},{"key":"2026092423160528300_vlag053-B25","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1084\/jem.169.3.1071","article-title":"Elastase inhibitor. Characterization of the human elastase inhibitor molecule associated with monocytes, macrophages, and neutrophils","volume":"169","author":"Remold-O\u2019Donnell","year":"1989","journal-title":"J. Exp. Med"},{"key":"2026092423160528300_vlag053-B26","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1165\/ajrcmb.13.3.7654387","article-title":"Inhibitory properties of recombinant human monocyte\/neutrophil elastase inhibitor","volume":"13","author":"Sugimori","year":"1995","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026092423160528300_vlag053-B27","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.smim.2017.12.005","article-title":"Immune regulation by monocytes","volume":"35","author":"Murray","year":"2018","journal-title":"Semin. Immunol"},{"key":"2026092423160528300_vlag053-B28","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1159\/000296507","article-title":"Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death","volume":"2","author":"Parihar","year":"2010","journal-title":"J Innate Immun"},{"key":"2026092423160528300_vlag053-B29","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1189\/jlb.0613331","article-title":"SerpinB1 regulates homeostatic expansion of IL-17+ gamma-delta and CD4+ Th17 cells","volume":"95","author":"Zhao","year":"2014","journal-title":"J Leukoc Biol"},{"key":"2026092423160528300_vlag053-B30","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/ni.2247","article-title":"Intrathymic programming of effector fates in three molecularly distinct \u03b3\u03b4 T cell subtypes","volume":"13","author":"Narayan","year":"2012","journal-title":"Nat Immunol"},{"key":"2026092423160528300_vlag053-B31","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1038\/ni.3437","article-title":"Innate-like functions of natural killer T cell subsets result from highly divergent gene programs","volume":"17","author":"Engel","year":"2016","journal-title":"Nat Immunol"},{"key":"2026092423160528300_vlag053-B32","doi-asserted-by":"publisher","first-page":"13116","DOI":"10.1038\/ncomms13116","article-title":"Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets","volume":"7","author":"Georgiev","year":"2016","journal-title":"Nat Commun"},{"key":"2026092423160528300_vlag053-B33","doi-asserted-by":"publisher","first-page":"562587","DOI":"10.3389\/fimmu.2020.562587","article-title":"Serpinb1a is dispensable for the development and cytokine response of invariant natural killer T cell subsets","volume":"11","author":"Leborgne","year":"2020","journal-title":"Front Immunol"}],"container-title":["ImmunoHorizons"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article-pdf\/10\/9\/vlag053\/71384101\/vlag053.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article-pdf\/10\/9\/vlag053\/71384101\/vlag053.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:16:16Z","timestamp":1790306176000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article\/doi\/10.1093\/immhor\/vlag053\/8834071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":33,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9,22]]}},"URL":"https:\/\/doi.org\/10.1093\/immhor\/vlag053","relation":{},"ISSN":["2573-7732"],"issn-type":[{"value":"2573-7732","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,9]]},"article-number":"vlag053"}}