Journal
ADVANCED SCIENCE
Volume 9, Issue 12, Pages -Publisher
WILEY
DOI: 10.1002/advs.202103675
Keywords
acute kidney injury; inflammation; macrophage; S100a9; single-cell RNA-seq; therapeutic target
Categories
Funding
- National Natural Science Foundation of China [91742205, 81625004, 82130021]
- Beijing Young Scientist Program [BJJWZYJH01201910001006]
- Peking University Clinical Scientist Program by the Fundamental Research Funds for the Central Universities
- CAMS Innovation Fund for Medical Sciences [2019-I2M-5-046]
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This study reveals the complementary roles of kidney resident macrophages (KRMs) and monocyte-derived infiltrated macrophages (IMs) in modulating tissue inflammation and promoting tissue repair in ischemia reperfusion injury induced acute kidney injury (IRI-AKI). S100a9(hi)Ly6c(hi) IMs are identified as early responders to AKI, mediating the initiation and amplification of kidney inflammation. Targeting S100a8/a9 signaling with small-molecule inhibitors demonstrates renal protective effects.
Acute kidney injury (AKI) is a complex clinical disorder associated with poor outcomes. Targeted regulation of the degree of inflammation has been a potential strategy for AKI management. Macrophages are the main effector cells of kidney inflammation. However, macrophage heterogeneity in ischemia reperfusion injury induced AKI (IRI-AKI) remains unclear. Using single-cell RNA sequencing of the mononuclear phagocytic system in the murine IRI model, the authors demonstrate the complementary roles of kidney resident macrophages (KRMs) and monocyte-derived infiltrated macrophages (IMs) in modulating tissue inflammation and promoting tissue repair. A unique population of S100a9(hi)Ly6c(hi) IMs is identified as an early responder to AKI, mediating the initiation and amplification of kidney inflammation. Kidney infiltration of S100A8/A9(+) macrophages and the relevance of renal S100A8/A9 to tissue injury is confirmed in human AKI. Targeting the S100a8/a9 signaling with small-molecule inhibitors exhibits renal protective effects represented by improved renal function and reduced mortality in bilateral IRI model, and decreased inflammatory response, ameliorated kidney injury, and improved long-term outcome with decreased renal fibrosis in the unilateral IRI model. The findings support S100A8/A9 blockade as a feasible and clinically relevant therapy potentially waiting for translation in human AKI.
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