ST2 Signaling Regulates Innate Immune Responses in Kidney Injury.

Introduction: Innate immune cells are critical in inflammation, repair, and fibrosis post-kidney injury. Nuclear-cytokine interleukin (IL)-33, which is released upon tissue damage, signals through IL-1-receptor-like-1 (IL1RL1 or ST2), expressed on many immune cells, including macrophages. However, macrophage regulation by IL-33/ST2 is incompletely understood. We hypothesized that ST2 plays a vital role in activating and/or mobilizing myeloid cells and macrophages to sites of injury. Methods: We performed acute and chronic ischemia-reperfusion injury (IRI) in mice with myeloid cell-specific deletion of ST2 (ST2 Results: Interestingly, ST2 deletion resulted in attenuated renal pathology in the acute renal IRI model, whereas in chronic IRI, the loss of ST2 exacerbated kidney injury, suggesting a role of ST2 in the resolution of chronic injury. RNA sequencing (RNASeq) analysis of bone-marrow-derived ST2 sufficient and deficient macrophages showed that loss of ST2 downregulated genes involved in oxidative phosphorylation and clearance of dead cells (efferocytosis). Indeed, the ST2-deficient macrophages had reduced phagocytosis activity. Further, Seahorse analysis revealed that ST2-deficient macrophages had compromised mitochondrial metabolism. Conclusions: We conclude that the IL-33/ST2 axis is essential for regulating macrophage function and contributes to regulating tissue homeostasis following renal injury.