Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis
Yuzi Tian, Shibin Qu, Hasan B. Alam, Aaron M. Williams, Zhenyu Wu, Qiufang Deng, Baihong Pan, Jing Zhou, Baoling Liu, Xiuzhen Duan, Jianjie Ma, Santanu Mondal, Paul R. Thompson, Kathleen A. Stringer, Theodore J. Standiford, Yongqing Li
Yuzi Tian, Shibin Qu, Hasan B. Alam, Aaron M. Williams, Zhenyu Wu, Qiufang Deng, Baihong Pan, Jing Zhou, Baoling Liu, Xiuzhen Duan, Jianjie Ma, Santanu Mondal, Paul R. Thompson, Kathleen A. Stringer, Theodore J. Standiford, Yongqing Li
View: Text | PDF
Research Article Infectious disease Inflammation

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

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.

Authors

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

×

Figure 7

Absence of the Pad2 gene inhibits Caspase-11–dependent noncanonical pyroptosis in BM-derived macrophages (BMDMs) and LPS-endotoxic model.

Options: View larger image (or click on image) Download as PowerPoint
Absence of the Pad2 gene inhibits Caspase-11–dependent noncanonical pyro...
(A) Representative Western blot images and densitometry quantification show expression of PAD2 in WT mouse BMDMs after noncanonical pyroptosis treatment. (B) LDH release in the supernatant of BMDMs after noncanonical pyroptosis treatment. (C) Representative Western blot images show Caspase-11 and GSDMD activation in the supernatant and cell lysate of BMDMs with or without noncanonical pyroptosis treatment. (D and E) Concentrations of IL-1α (D) and TNF-α (E) in the supernatant of BMDMs with or without noncanonical pyroptosis treatment (n = 3/group). (F) Kaplan-Meier survival curve of WT and Pad2–/– mouse in LPS-endotoxic mouse model (n = 14–17/group). (G and H) Concentrations of IL-1α (G) and TNF-α (H) in the serum of WT and Pad2–/– mice with or without LPS challenge (n = 3, 8, 3, and 7 for each group, respectively). Results in A–E were representative of at least 3 independent experiments. Data are expressed as mean ± SEM. Data with 2 groups were analyzed using unpaired 2-tailed Student’s t test (B). Three or more groups were analyzed by 1-way (A) or 2-way (D, E, G, and H) ANOVA with Bonferroni’s multiple comparisons test. Survival curve were analyzed by log-rank test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. SN, supernatant.