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

Yuzi Tian,Hasan B Alam,Theodore J Standiford,Yongqing Li,Baihong Pan,Xiuzhen Duan,Paul R Thompson,Shibin Qu,Santanu Mondal,Jianjie Ma,Qiufang Deng,Jing Zhou,Baoling Liu,Kathleen A Stringer,Zhenyu Wu,Aaron M Williams

doi:10.1172/jci.insight.138873

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.

Highlights

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [1]
Since acute respiratory distress syndrome (ARDS) is a common complication in sepsis, we measured levels of PAD2 in bronchoalveolar lavage fluid (BALF) that was collected from patients within 7 days of the diagnosis of sepsis-induced ARDS
Like Pad2–/– mice, the bacterial clearance in the peritoneal cavity, blood, and spleen of Caspase-11–/– mice (Supplemental Figure 6A) was significantly increased, along with an increase of macrophage numbers (Supplemental Figure 6B) compared with WT mice. These results indicate that the loss of Pad2 function results in a reduction of noncanonical pyroptosis, increasing viable macrophage numbers that may contribute to the observed decrease in bacterial load and inflammation after CLP in Pad2–/– versus WT mice

Summary

Introduction

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. As of 2017, sepsis accounted for 11 million deaths worldwide [2]. Many efforts have focused on developing therapeutic targets, but relatively effective treatments for sepsis are lacking. In defense against microbial infection, innate immune cells are activated, causing neutrophil extracellular trap (NET) formation (NETosis, a programmed neutrophil death) and macrophage pyroptosis (an inflammatory cell death). NETosis sequesters bacteria for pathogen inactivation [3], and pyroptosis is an antimicrobial response that mainly takes place in macrophages. Uncontrolled immune cell death has recently been considered as a significant contributing factor to sepsis pathogenesis [4,5,6], it is presently unknown whether manipulation of the regulation of NETosis and/or pyroptosis influences sepsis progression

Methods

Results

Conclusion