Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis

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dc.contributor.authorTian, Yuzi
dc.contributor.authorMondal, Santanu
dc.contributor.authorThompson, Paul R
dc.contributor.authorLi, Yongqing
dc.contributor.departmentThompson Lab
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.date2022-08-11T08:09:57.000
dc.date.accessioned2022-08-23T16:50:17Z
dc.date.available2022-08-23T16:50:17Z
dc.date.issued2020-10-15
dc.date.submitted2020-12-16
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractPeptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2-/- or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11-dependent pyroptosis in vivo and in vitro. Suppression of PAD2 expression reduced inflammation and increased macrophage bactericidal activity. In contrast to Pad2-/-, Pad4 deficiency enhanced activation of Caspase-11-dependent pyroptosis in BM-derived macrophages and displayed no survival improvement in a mouse sepsis model. Collectively, our findings highlight the potential of PAD2 as an indicative marker and therapeutic target for sepsis.
dc.identifier.citation<p>Tian Y, Qu S, Alam HB, Williams AM, Wu Z, Deng Q, Pan B, Zhou J, Liu B, Duan X, Ma J, Mondal S, Thompson PR, Stringer KA, Standiford TJ, Li Y. Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis. JCI Insight. 2020 Oct 15;5(20):e138873. doi: 10.1172/jci.insight.138873. PMID: 33055424; PMCID: PMC7605547. <a href="https://doi.org/10.1172/jci.insight.138873">Link to article on publisher's site</a></p>
dc.identifier.contextkey20637418
dc.identifier.doi10.1172/jci.insight.138873
dc.identifier.issn2379-3708 (Linking)
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4423
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5453&amp;context=oapubs&amp;unstamped=1
dc.identifier.pmid33055424
dc.identifier.submissionpathoapubs/4423
dc.identifier.urihttps://hdl.handle.net/20.500.14038/41631
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=33055424&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright: © 2020, Tian et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.source.issue20
dc.source.journaltitleJCI insight
dc.source.pagese138873
dc.source.volume5
dc.subjectInfectious disease
dc.subjectInflammation
dc.subjectMolecular biology
dc.subjectMolecular pathology
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectImmunopathology
dc.subjectImmunotherapy
dc.subjectMolecular Biology
dc.titlePeptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis
dc.typeJournal Article
dspace.entity.typePublication
html.description.abstract<p>Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2-/- or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11-dependent pyroptosis in vivo and in vitro. Suppression of PAD2 expression reduced inflammation and increased macrophage bactericidal activity. In contrast to Pad2-/-, Pad4 deficiency enhanced activation of Caspase-11-dependent pyroptosis in BM-derived macrophages and displayed no survival improvement in a mouse sepsis model. Collectively, our findings highlight the potential of PAD2 as an indicative marker and therapeutic target for sepsis.</p>
refterms.dateFOA2022-08-23T16:50:17Z
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