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 5

Absence of the Pad2 gene inhibits NET formation both in vivo and in vitro.

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Absence of the Pad2 gene inhibits NET formation both in vivo and in vitr...
WT and Pad2–/– mice were subjected to CLP. (A and B) The concentrations of dsDNA in mouse serum (n = 3 for WT mice without CLP group, n = 5 for WT mice with CLP group, n = 3 for Pad2–/– mice without CLP group, n = 7 for Pad2–/– mice with CLP group) (A) and peritoneal lavage (n = 4 for WT mice without CLP group, n = 9 for WT mice with CLP group, n = 3 for Pad2–/– mice without CLP group, and n = 8 for Pad2–/– mice with CLP group) (B) after 24 hours. BM neutrophils were isolated from WT and Pad2–/– mice and were treated with A23187 or PMA. (C) NET formation in response to calcium ionophore and PMA in WT and Pad2–/– neutrophils at different time points (n = 3–5/group). (D) Representative immunofluorescence images of the NET formation in WT and Pad2–/– neutrophils after vehicle, Ca2+ ionophore (A23187), or PMA treatment for 3.5 hours. (E and F) Quantification results of immunofluorescence images (n = 6/group). (G) Levels of myeloperoxidase-DNA (MPO-DNA) in cell supernatant of WT and Pad2–/– neutrophils after vehicle, A23187or PMA treatment for 3.5 hours. Results are representative of 2 independent experiments (C–G). Data are expressed as mean ± SEM. Data were analyzed by 2-way ANOVA with Bonferroni’s multiple comparisons test (A–C and E–G). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Scale bar: 50 μm. Ve, vehicle.