{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Privratsky JR"],"funding":["BLRD VA","NIDDK NIH HHS","NIGMS NIH HHS"],"pagination":["514-528"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9974788"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["103(3)"],"pubmed_abstract":["The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. Kidney macrophages consist of both F4/80<sup>hi</sup> and CD11b<sup>hi</sup> cells. The role of macrophage subpopulations in septic AKI pathogenesis remains unclear. As F4/80<sup>hi</sup> macrophages are reported to contribute to immunomodulation following injury, we hypothesized that selective depletion of F4/80<sup>hi</sup> macrophages would worsen septic AKI. F4/80<sup>hi</sup> macrophages were depleted via diphtheria toxin injection in CD11cCre(+)/CX3CR1<sup>dtr/wt</sup> (F4/80 MKO mice) compared to CD11cCre(-)/CX3CR1<sup>dtr/wt</sup> (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<sup>hi</sup> 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<sup>hi</sup> 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."],"journal":["Kidney international"],"pubmed_title":["A macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury."],"pmcid":["PMC9974788"],"funding_grant_id":["I01 BX000893","R01 DK118019","K08 GM132689","R01 DK123097","R01 DK131065"],"pubmed_authors":["Privratsky JR","Souma T","Crowley SD","Lu X","Kitai H","Ren J","Chen Y","Fradin H","Ide S"],"additional_accession":[]},"is_claimable":false,"name":"A macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury.","description":"The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. Kidney macrophages consist of both F4/80<sup>hi</sup> and CD11b<sup>hi</sup> cells. The role of macrophage subpopulations in septic AKI pathogenesis remains unclear. As F4/80<sup>hi</sup> macrophages are reported to contribute to immunomodulation following injury, we hypothesized that selective depletion of F4/80<sup>hi</sup> macrophages would worsen septic AKI. F4/80<sup>hi</sup> macrophages were depleted via diphtheria toxin injection in CD11cCre(+)/CX3CR1<sup>dtr/wt</sup> (F4/80 MKO mice) compared to CD11cCre(-)/CX3CR1<sup>dtr/wt</sup> (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<sup>hi</sup> 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<sup>hi</sup> 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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Mar","modification":"2026-06-01T17:21:56.379Z","creation":"2025-04-03T23:49:48.66Z"},"accession":"S-EPMC9974788","cross_references":{"pubmed":["36334787"],"doi":["10.1016/j.kint.2022.10.008"]}}