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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\u2010AKI) remains unclear. Using single\u2010cell 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\u2010derived infiltrated macrophages (IMs) in modulating tissue inflammation and promoting tissue repair. A unique population of S100a9\n                    <jats:sup>hi<\/jats:sup>\n                    Ly6c\n                    <jats:sup>hi<\/jats:sup>\n                    IMs is identified as an early responder to AKI, mediating the initiation and amplification of kidney inflammation. Kidney infiltration of S100A8\/A9\n                    <jats:sup>+<\/jats:sup>\n                    macrophages and the relevance of renal S100A8\/A9 to tissue injury is confirmed in human AKI. Targeting the S100a8\/a9 signaling with small\u2010molecule 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\u2010term 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.\n                  <\/jats:p>","DOI":"10.1002\/advs.202103675","type":"journal-article","created":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T05:49:52Z","timestamp":1643867392000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":150,"title":["Single Cell RNA Sequencing Identifies a Unique Inflammatory Macrophage Subset as a Druggable Target for Alleviating Acute Kidney Injury"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1049-4273","authenticated-orcid":false,"given":"Weijian","family":"Yao","sequence":"first","affiliation":[{"name":"Renal Division Peking University Institute of Nephrology Key Laboratory of Renal Disease\u2010Ministry of Health of China Key Laboratory of CKD Prevention and Treatment (Peking University)\u2010Ministry of Education of 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