Single-cell RNA sequencing identifies a proinflammatory S100a8/a9+ macrophage subset contributing to acute kidney injury.

OBJECTIVE

Macrophages represent a heterogeneous cell population in the kidney. However, macrophage subsets and their role in endotoxemia-induced acute kidney injury (AKI) remain elucidated.

MATERIAL AND

METHODS

Single-cell RNA sequencing was performed to identify macrophage subpopulations in mouse kidney following lipopolysaccharide (LPS) challenge. AKI was induced by LPS treatment or renal ischemia reperfusion injury in wild-type or S100a9-/- mice. Silencing or overexpression of S100a9 was carried out to assess its function and contribution to LPS-induced inflammation and AKI. In addition, bone marrow cells from S100a9-/- mice were injected into the recipient mice to determine the effect of S100a9 deletion in macrophage differentiation and renal inflammatory injury.

RESULTS

By using single-cell RNA sequencing, we identified a unique S100a8/a9+Ly6chigh proinflammatory macrophage subpopulation in mouse kidney following LPS challenge. LPS administration induced the infiltration of Ly6c+ macrophages into kidney tissues and significantly upregulated the expression of S100a8 and S100a9. S100a9 deletion downregulated S100a8 expression, decreased CD11b+Ly6chigh macrophages, and suppressed proinflammatory cytokine production in the kidney, attenuating LPS or ischemia reperfusion-induced renal inflammation and AKI. Bone marrow transplantation from S100a9-/- mice donors, but not from wild-type mice donors, reduced infiltration of CD11b+Ly6chigh macrophages and renal inflammatory injury. S100a8/a9 overexpression activated the nuclear factor-κB signaling pathway and promoted the production of proinflammatory cytokines in macrophages.

CONCLUSIONS

S100a8/a9 plays a regulatory role in CD11b+Ly6chigh macrophage population differentiation, contributing to endotoxemia-induced AKI. S100a8/a9 blockade may be a novel therapeutic strategy for the prevention or attenuation of AKI.