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
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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

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Figure 1

PAD2 protein is increased in patients with sepsis and a murine model of sepsis.

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PAD2 protein is increased in patients with sepsis and a murine model of ...
(A) Levels of serum PAD2 protein in healthy controls and patients with sepsis. Serum samples from patients with sepsis collected at enrollment, 24 hours, and 48 hours (n = 13–18/group) were assayed. (B) Correlation of serum concentrations of PAD2 protein and lactate in patients with sepsis at enrollment (n = 17). (C) Correlation of serum concentrations of PAD2 protein and procalcitonin (PCT) in patients with sepsis at enrollment (n = 17). The line in the graphs represents the linear fit. (D) Levels of PAD2 protein in bronchoalveolar lavage fluid from healthy controls and patients with ARDS (n = 5 for healthy controls and n = 14 for patients with sepsis-induced ARDS). (E) Levels of serum PAD2 protein in sham and CLP mice at 12 hours and 24 hours (n = 4–6/group). (F) Western blot results show the expression of PAD2 protein in mouse lung tissue with or without CLP (n = 3). Nonnormality data are expressed as minimal to maximal value with quantile range (A and D). Data in E are expressed as mean ± SEM. Data with 3 or more groups were analyzed by Kruskal-Wallis test with Dunnett’s multiple comparisons test (A) or 1-way ANOVA with Bonferroni’s multiple comparisons test (E). Two groups were analyzed using Mann-Whitney U test (D). Correlations between concentrations of PAD2 and lactate or PCT were analyzed using Pearson correlation model. *P < 0.05, **P < 0.01, ***P < 0.001. The green dots in A and D were values below the lower limit of quantification of the ELISA kit but based on standard curve back calculation.