ST2 Signaling Regulates Innate Immune Responses in Kidney Injury

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.

We performed acute and chronic ischemia-reperfusion injury (IRI) in mice with myeloid cell-specific deletion of ST2 (ST2^fl/fl.LysM^Cre) to examine the role of myeloid cells ST2 expression in renal injury. The structure and function of the kidney were probed using flow cytometry, histology, immunohistochemistry, quantitative gene expression, and biochemical analysis. The invitro efferocytosis assay, RNA Seq, and Seahorse assay were carried out using bone-marrow-derived macrophages.

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.

We conclude that the IL-33/ST2 axis is essential for regulating macrophage function and contributes to regulating tissue homeostasis following renal injury.