UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date

2020-10-15

Document Type

Article

Disciplines

Biochemistry | Enzymes and Coenzymes | Immunopathology | Immunotherapy | Molecular Biology

Abstract

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.

Keywords

Infectious disease, Inflammation, Molecular biology, Molecular pathology

Rights and Permissions

Copyright: © 2020, Tian et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

DOI of Published Version

10.1172/jci.insight.138873

Source

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. Link to article on publisher's site

Journal/Book/Conference Title

JCI insight

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

33055424

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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