Department of Biochemistry and Molecular Pharmacology; Thompson Lab
Biochemistry | Enzymes and Coenzymes | Immunopathology | Immunotherapy | Molecular Biology
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.
Infectious disease, Inflammation, Molecular biology, Molecular pathology
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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
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
Tian Y, Mondal S, Thompson PR, Li Y. (2020). Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis. Open Access Publications by UMMS Authors. https://doi.org/10.1172/jci.insight.138873. Retrieved from https://escholarship.umassmed.edu/oapubs/4423
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.