biostudies-literaturePrivratsky JRBLRD VANIDDK NIH HHSNIGMS NIH HHS514-528https://www.ebi.ac.uk/biostudies/studies/S-EPMC9974788biostudies-literatureUnknown103(3)The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. Kidney macrophages consist of both F4/80^hi and CD11b^hi cells. The role of macrophage subpopulations in septic AKI pathogenesis remains unclear. As F4/80^hi macrophages are reported to contribute to immunomodulation following injury, we hypothesized that selective depletion of F4/80^hi macrophages would worsen septic AKI. F4/80^hi macrophages were depleted via diphtheria toxin injection in CD11cCre(+)/CX3CR1^dtr/wt (F4/80 MKO mice) compared to CD11cCre(-)/CX3CR1^dtr/wt (F4/80 MWT) mice. F4/80 MWT and F4/80 MKO mice were subjected to sham or cecal ligation and puncture to induce sepsis. Compared to F4/80 MWT mice, F4/80 MKO mice displayed worsened septic AKI at 24 hours as measured by serum creatinine and histologic injury scoring. Kidneys from F4/80 MKO mice elaborated higher kidney interleukin-6 levels. Mechanistically, single cell RNA sequencing identified a macrophage-endothelial cell immunoregulatory axis that underlies interleukin-6 expression. F4/80^hi macrophages expressed interleukin-1 receptor antagonist and limited interleukin-6 expression in endothelial cells. In turn, anti-interleukin-6 therapy ameliorated septic AKI in F4/80 MKO mice. Thus, F4/80^hi macrophages express interleukin-1 receptor antagonist and constrain interleukin-6 generation from endothelial cells to limit septic AKI, representing a targetable cellular crosstalk in septic AKI. These findings are particularly relevant owing to the efficacy of anti-interleukin-6 therapies during COVID-19 infection, a disease associated with high rates of AKI and endothelial dysfunction.Kidney internationalA macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury.PMC9974788I01 BX000893R01 DK118019K08 GM132689R01 DK123097R01 DK131065Privratsky JRSouma TCrowley SDLu XKitai HRen JChen YFradin HIde SfalseA macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury.The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. Kidney macrophages consist of both F4/80^hi and CD11b^hi cells. The role of macrophage subpopulations in septic AKI pathogenesis remains unclear. As F4/80^hi macrophages are reported to contribute to immunomodulation following injury, we hypothesized that selective depletion of F4/80^hi macrophages would worsen septic AKI. F4/80^hi macrophages were depleted via diphtheria toxin injection in CD11cCre(+)/CX3CR1^dtr/wt (F4/80 MKO mice) compared to CD11cCre(-)/CX3CR1^dtr/wt (F4/80 MWT) mice. F4/80 MWT and F4/80 MKO mice were subjected to sham or cecal ligation and puncture to induce sepsis. Compared to F4/80 MWT mice, F4/80 MKO mice displayed worsened septic AKI at 24 hours as measured by serum creatinine and histologic injury scoring. Kidneys from F4/80 MKO mice elaborated higher kidney interleukin-6 levels. Mechanistically, single cell RNA sequencing identified a macrophage-endothelial cell immunoregulatory axis that underlies interleukin-6 expression. F4/80^hi macrophages expressed interleukin-1 receptor antagonist and limited interleukin-6 expression in endothelial cells. In turn, anti-interleukin-6 therapy ameliorated septic AKI in F4/80 MKO mice. Thus, F4/80^hi macrophages express interleukin-1 receptor antagonist and constrain interleukin-6 generation from endothelial cells to limit septic AKI, representing a targetable cellular crosstalk in septic AKI. These findings are particularly relevant owing to the efficacy of anti-interleukin-6 therapies during COVID-19 infection, a disease associated with high rates of AKI and endothelial dysfunction.2023-01-01T00:00:00Z2023 Mar2026-06-01T17:21:56.379Z2025-04-03T23:49:48.66ZS-EPMC99747883633478710.1016/j.kint.2022.10.008