title: Distinct macrophage phenotypes contribute to kidney injury and repair.
abstract: The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1- and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifnγ-stimulated, bone marrow-derived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFNγ-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4-stimulated macrophages with an M2 phenotype, but not IFNγ-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFNγ-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.
authors.affiliation: Yale University School of Medicine, 333 Cedar Street, PO Box 208029, New Haven, CT 06510, USA.
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.forename: Sarah
authors.initials: S
authors.lastname: Huen
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishio
authors.forename: Saori
authors.initials: S
authors.lastname: Nishio
authors.forename: Heung Kyu
authors.initials: HK
authors.lastname: Lee
authors.forename: Bum-Soon
authors.initials: BS
authors.lastname: Choi
authors.forename: Christiana
authors.initials: C
authors.lastname: Ruhrberg
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Cantley
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000032:analysis; D007668:Kidney / Q000098:blood supply; D007684:Kidney Tubules / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015427:Reperfusion Injury / Q000209:etiology* / Q000503:physiopathology
chemical_list: D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D015847:Interleukin-4; D007371:Interferon-gamma