PMID- 31315923 OWN - NLM STAT- MEDLINE DCOM- 20200528 LR - 20201001 IS - 1533-3450 (Electronic) IS - 1046-6673 (Print) IS - 1046-6673 (Linking) VI - 30 IP - 10 DP - 2019 Oct TI - Tubular GM-CSF Promotes Late MCP-1/CCR2-Mediated Fibrosis and Inflammation after Ischemia/Reperfusion Injury. PG - 1825-1840 LID - 10.1681/ASN.2019010068 [doi] AB - BACKGROUND: After bilateral kidney ischemia/reperfusion injury (IRI), monocytes infiltrate the kidney and differentiate into proinflammatory macrophages in response to the initial kidney damage, and then transition to a form that promotes kidney repair. In the setting of unilateral IRI (U-IRI), however, we have previously shown that macrophages persist beyond the time of repair and may promote fibrosis. METHODS: Macrophage homing/survival signals were determined at 14 days after injury in mice subjected to U-IRI and in vitro using coculture of macrophages and tubular cells. Mice genetically engineered to lack Ccr2 and wild-type mice were treated +/-CCR2 antagonist RS102895 and subjected to U-IRI to quantify macrophage accumulation, kidney fibrosis, and inflammation 14 and 30 days after the injury. RESULTS: Failure to resolve tubular injury after U-IRI results in sustained expression of granulocyte-macrophage colony-stimulating factor by renal tubular cells, which directly stimulates expression of monocyte chemoattractant protein-1 (Mcp-1) by macrophages. Analysis of CD45(+) immune cells isolated from wild-type kidneys 14 days after U-IRI reveals high-level expression of the MCP-1 receptor Ccr2. In mice lacking Ccr2 and wild-type mice treated with RS102895, the numbers of macrophages, dendritic cells, and T cell decreased following U-IRI, as did the expression of profibrotic growth factors and proimflammatory cytokines. This results in a reduction in extracellular matrix and kidney injury markers. CONCLUSIONS: GM-CSF-induced MCP-1/CCR2 signaling plays an important role in the cross-talk between injured tubular cells and infiltrating immune cells and myofibroblasts, and promotes sustained inflammation and tubular injury with progressive interstitial fibrosis in the late stages of U-IRI. CI - Copyright (c) 2019 by the American Society of Nephrology. FAU - Xu, Leyuan AU - Xu L AUID- ORCID: 0000-0002-3071-9206 AD - Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; and leyuan.xu@yale.edu lloyd.cantley@yale.edu. FAU - Sharkey, Diana AU - Sharkey D AD - Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut. FAU - Cantley, Lloyd G AU - Cantley LG AD - Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; and leyuan.xu@yale.edu lloyd.cantley@yale.edu. LA - eng GR - K01 DK120783/DK/NIDDK NIH HHS/United States GR - R01 DK093771/DK/NIDDK NIH HHS/United States GR - T32 DK007276/DK/NIDDK NIH HHS/United States GR - UL1 TR001863/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190717 PL - United States TA - J Am Soc Nephrol JT - Journal of the American Society of Nephrology : JASN JID - 9013836 RN - 0 (Ccl2 protein, mouse) RN - 0 (Ccr2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Receptors, CCR2) RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) SB - IM MH - Animals MH - Cells, Cultured MH - Chemokine CCL2/*physiology MH - Fibrosis/etiology MH - Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis/*physiology MH - Inflammation/*etiology MH - Kidney/*blood supply/*pathology MH - Kidney Tubules/cytology/metabolism MH - Macrophages MH - Mice MH - Receptors, CCR2/*physiology MH - Reperfusion Injury/*complications PMC - PMC6779361 OTO - NOTNLM OT - CCR2 OT - GM-CSF OT - MCP-1 OT - macrophage OT - renal fibrosis EDAT- 2019/07/19 06:00 MHDA- 2020/05/29 06:00 PMCR- 2020/10/01 CRDT- 2019/07/19 06:00 PHST- 2019/01/23 00:00 [received] PHST- 2019/05/22 00:00 [accepted] PHST- 2019/07/19 06:00 [pubmed] PHST- 2020/05/29 06:00 [medline] PHST- 2019/07/19 06:00 [entrez] PHST- 2020/10/01 00:00 [pmc-release] AID - ASN.2019010068 [pii] AID - 2019010068 [pii] AID - 10.1681/ASN.2019010068 [doi] PST - ppublish SO - J Am Soc Nephrol. 2019 Oct;30(10):1825-1840. doi: 10.1681/ASN.2019010068. Epub 2019 Jul 17.