Interleukin-33 Promotes Neutrophil Extracellular Trap Formation To Aggravate Renal Ischemia-Reperfusion Injury Through ST2/PI3K/Akt and ST2/PAD4 Pathways

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Renal ischemia-reperfusion injury (IRI) triggers a sterile immune response, primarily mediated by the innate immune system. Interleukin-33 (IL-33) promotes neutrophil infiltration during inflammatory processes, and neutrophils play a critical role in renal IRI pathology. This study aims to elucidate the mechanisms of IL-33 in neutrophil extracellular trap (NET) formation during renal IRI. The association between IL-33 and NET formation was investigated using suppression of tumorigenicity 2 (ST2) knockout (KO) mice, RNA sequencing, and pharmacological interventions. Results revealed that compared with preoperative levels, postoperative serum IL-33 and NET formation were elevated and positively correlated in patients undergoing renal transplantation. Similarly, the mouse model of renal I/R exhibited increased IL-33 expression and NET formation, which were also highly correlated. Administration of recombinant IL-33 during renal I/R enhanced NET formation and worsened renal IRI. However, treatment with an anti-IL-33 monoclonal antibody decreased NET formation and mitigated renal IRI. ST2 KO mice exhibited reduced NET formation and increased protection against renal IRI compared to control mice after renal I/R. In vitro studies showed that IL-33 dose-dependently promoted NET formation in neutrophils. Mechanistically, IL-33-induced NET formation was markedly reduced in ST2 KO mouse-derived neutrophils. Furthermore, RNA sequencing results revealed that IL-33-induced NET formation was mediated via ST2/ PI3K/Akt and ST2/peptidylarginine deiminase 4 (PAD4) signaling pathways. Inhibition of these pathways significantly suppressed IL-33-induced NET formation. In summary, this study demonstrates that IL-33/ST2 signaling exacerbates renal IRI by amplifying NETs. Targeting the IL-33/ST2 axis and inhibiting NET formation offers promising therapeutic strategies for preventing and treating renal IRI.