Inhibition of PAD2 Improves Survival in a Mouse Model of Lethal LPS-Induced Endotoxic Shock
Department of Biochemistry and Molecular Pharmacology; Thompson Lab
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Enzymes and Coenzymes | Pathological Conditions, Signs and Symptoms
Endotoxemia induced by lipopolysaccharide (LPS) is an extremely severe syndrome identified by global activation of inflammatory responses. Neutrophil extracellular traps (NETs) play an important role in the development of endotoxemia. Histone hypercitrullination catalyzed by peptidylarginine deiminases (PADs) is a key step of NET formation. We have previously demonstrated that simultaneous inhibition of PAD2 and PAD4 with pan-PAD inhibitors can decrease NETosis and improve survival in a mouse model of LPS-induced endotoxic shock. However, the effects of PAD2 specific inhibition during NETosis and endotoxic shock are poorly understood. Therefore, in the present study, we aimed to investigate the effect of the specific PAD2 or PAD4 inhibitor on LPS-induced endotoxic shock in mice. We found that PAD2 inhibition but not PAD4 inhibition improves survival. Also, the levels of proinflammatory cytokines and NETosis were significantly reduced by PAD2 inhibitor. To our knowledge, this study demonstrates for the first time that PAD2 inhibition can reduce NETosis, decrease inflammatory cytokine production, and protect against endotoxin-induced lethality. Our findings provided a novel therapeutic strategy for the treatment of endotoxic shock.
LPS-induced endotoxic shock, NETosis, PAD2, acute lung injury, selective PAD2 inhibitor
DOI of Published Version
Wu Z, Deng Q, Pan B, Alam HB, Tian Y, Bhatti UF, Liu B, Mondal S, Thompson PR, Li Y. Inhibition of PAD2 Improves Survival in a Mouse Model of Lethal LPS-Induced Endotoxic Shock. Inflammation. 2020 Aug;43(4):1436-1445. doi: 10.1007/s10753-020-01221-0. PMID: 32239392. Link to article on publisher's site
Wu Z, Deng Q, Pan B, Alam HB, Tian Y, Bhatti UF, Liu B, Mondal S, Thompson PR, Li Y. (2020). Inhibition of PAD2 Improves Survival in a Mouse Model of Lethal LPS-Induced Endotoxic Shock. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1007/s10753-020-01221-0. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1722