| First Author | Iwata Y | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 9 | Pages | 4568-80 |
| PubMed ID | 22467656 | Mgi Jnum | J:188447 |
| Mgi Id | MGI:5440559 | Doi | 10.4049/jimmunol.1102154 |
| Citation | Iwata Y, et al. (2012) Aberrant macrophages mediate defective kidney repair that triggers nephritis in lupus-susceptible mice. J Immunol 188(9):4568-80 |
| abstractText | CSF-1, required for macrophage (Mo) survival, proliferation, and activation, is upregulated in the tubular epithelial cells (TECs) during kidney inflammation. CSF-1 mediates Mo-dependent destruction in lupus-susceptible mice with nephritis and, paradoxically, Mo-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" Mo shifts toward the M2 "healer" phenotype in lupus-resistant mice after I/R, but M1 Mo 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 Mo inherently poised to destroy the kidney in MRL-Fas(lpr) mice. In conclusion, I/R induces CSF-1 in injured TECs that expands aberrant Mo (M1 phenotype), mediating defective renal repair and nonresolving inflammation, and thereby hastens the onset of lupus nephritis. |
