title: Aberrant macrophages mediate defective kidney repair that triggers nephritis in lupus-susceptible mice.
abstract: CSF-1, required for macrophage (Mø) survival, proliferation, and activation, is upregulated in the tubular epithelial cells (TECs) during kidney inflammation. CSF-1 mediates Mø-dependent destruction in lupus-susceptible mice with nephritis and, paradoxically, Mø-dependent renal repair in lupus-resistant mice after transient ischemia/reperfusion injury (I/R). We now report that I/R leads to defective renal repair, nonresolving inflammation, and, in turn, early-onset lupus nephritis in preclinical MRL/MpJ-Faslpr/Fas(lpr) mice (MRL-Fas(lpr) mice). Moreover, defective renal repair is not unique to MRL-Fas(lpr) mice, as flawed healing is a feature of other lupus-susceptible mice (Sle 123) and MRL mice without the Fas(lpr) mutation. Increasing CSF-1 hastens renal healing after I/R in lupus-resistant mice but hinders healing, exacerbates nonresolving inflammation, and triggers more severe early-onset lupus nephritis in MRL-Fas(lpr) mice. Probing further, the time-related balance of M1 "destroyer" Mø shifts toward the M2 "healer" phenotype in lupus-resistant mice after I/R, but M1 Mø continue to dominate in MRL-Fas(lpr) mice. Moreover, hypoxic TECs release mediators, including CSF-1, that are responsible for stimulating the expansion of M1 Mø inherently poised to destroy the kidney in MRL-Fas(lpr) mice. In conclusion, I/R induces CSF-1 in injured TECs that expands aberrant Mø (M1 phenotype), mediating defective renal repair and nonresolving inflammation, and thereby hastens the onset of lupus nephritis.
authors.affiliation: Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Iwata
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Boström
authors.forename: Julia
authors.initials: J
authors.lastname: Menke
authors.forename: Whitney A
authors.initials: WA
authors.lastname: Rabacal
authors.forename: Laurence
authors.initials: L
authors.lastname: Morel
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.forename: Vicki R
authors.initials: VR
authors.lastname: Kelley
mesh_terms: D000818:Animals; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D009154:Mutation; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C491899:Fas protein, mouse; D019014:fas Receptor; D016173:Macrophage Colony-Stimulating Factor