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  • Title: Aberrant macrophages mediate defective kidney repair that triggers nephritis in lupus-susceptible mice.
    Author: Iwata Y, Boström EA, Menke J, Rabacal WA, Morel L, Wada T, Kelley VR.
    Journal: J Immunol; 2012 May 01; 188(9):4568-80. PubMed ID: 22467656.
    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.
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