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

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...

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Bibliographic Details
Published in:JCI insight 2020-10, Vol.5 (20)
Main Authors: Tian, Yuzi, Qu, Shibin, Alam, Hasan B, Williams, Aaron M, Wu, Zhenyu, Deng, Qiufang, Pan, Baihong, Zhou, Jing, Liu, Baoling, Duan, Xiuzhen, Ma, Jianjie, Mondal, Santanu, Thompson, Paul R, Stringer, Kathleen A, Standiford, Theodore J, Li, Yongqing
Format: Article
Language:English
Subjects:
Acute Lung Injury - drug therapy
Acute Lung Injury - etiology
Acute Lung Injury - genetics
Acute Lung Injury - pathology
Animals
Autoimmune Diseases - blood
Autoimmune Diseases - genetics
Autoimmune Diseases - pathology
Biomarkers - blood
Caspases, Initiator - genetics
Extracellular Traps - genetics
Gene Expression Regulation - genetics
Humans
Infectious disease
Inflammation
Inflammation - genetics
Inflammation - pathology
Macrophages - metabolism
Macrophages - pathology
Mice
Protein-Arginine Deiminase Type 2 - antagonists & inhibitors
Protein-Arginine Deiminase Type 2 - genetics
Pyroptosis - genetics
Sepsis - blood
Sepsis - complications
Sepsis - genetics
Sepsis - pathology
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Summary: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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.138873