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.

Peptidylarginine Deiminase 2 in Host Immunity: Current Insights and Perspectives

“…As expected, the employment of a selective PAD2 inhibitor in the same model of LPS-induced endotoxic shock significantly increased survival (70). Thereafter, our studies further demonstrated that the knockout of Pad2 can improve survival in CLP-induced sepsis and PA-sepsis (59,103). Therefore, it can be inferred that PAD2 likely acts as a critical mediator in the pathogenesis of sepsis.…”

Role of Neutrophils on the Ocular Surface

“…Hypercitrullination in synovial fluid and anti-citrullinated protein antibodies in plasma are found in rheumatoid arthritis [ 44 ], suggesting that the hypercitrullinated molecules may serve as autoantigen. PAD2 and PAD4 are potential biomarkers and therapeutic targets of sepsis [ 45 ]. PAD4 inhibitor block neutrophil extracellular trap formation [ 46 ], reducing bleomycin fibrosis [ 47 , 48 ].…”

Icariside II regulates TLR4/NF-κB signaling pathway to improve septic lung injury

“…Here, we constructed the sepsis model of C57BL/6 mice by the use of LPS, and the symptoms of ALI were noticed in the model. The first mock exam has been widely used in the pathogenesis and drug screening of sepsis induced acute lung injury [18]. This animal model has several advantages, such as simple steps and no inoculation [18].…”

“…The first mock exam has been widely used in the pathogenesis and drug screening of sepsis induced acute lung injury [18]. This animal model has several advantages, such as simple steps and no inoculation [18]. Additionally, it could also induce the animal to produce a large number of cytokines, similar to that in patients.…”

“…The therapeutic function of traditional Chinese medicine on Sepsis and ALI have been widely reported [14,18]. As an effective constituent of traditional Chinese medicine Epimedii, ICA II has shown multiple biological activities including antioxidant, anti-inflammatory, and anti-apoptotic [14].…”