Chemokine expression precedes inflammatory cell infiltration and chemokine receptor and cytokine expression during the initiation of murine lupus nephritis.
Lupus nephritis is characterized by immune complex deposition and inflammatory cell infiltration. Therefore, the initiation and progression of lupus nephritis in MRL/MpJ Fas(lpr/lpr) (MRL/lpr) mice were investigated, with a focus on the expression of several chemokines and chemokine receptors. Mice were monitored for proteinuria from 6 to 20 wk of age, and kidneys were examined every 2 wk by light microscopy, electron microscopy, and immunohistologic analyses. Furthermore, the expression of chemokines, chemokine receptors, and proinflammatory cytokines was analyzed in ribonuclease protection assays. MRL/lpr mice demonstrated increased expression of monocyte chemoattractant protein-1, regulated upon activation, normal T cell-expressed and -secreted protein, inducible protein of 10 kD, and macrophage inflammatory protein-1beta at week 8. At that time point, levels of circulating and glomerular immune complexes were increased, and no proteinuria or histopathologic signs of renal damage could be observed. As assessed in immunohistochemical and in situ hybridization analyses, monocyte chemoattractant protein-1 and regulated upon activation, normal T cell-expressed and -secreted protein expression was preferentially located in the glomeruli and interstitium. Mononuclear cell infiltration of the kidney was observed by weeks 10 to 12. At week 12, the renal expression of chemokine receptor 1 (CCR1), CCR2, and CCR5 was increased, mice became proteinuric, and renal damage was histologically evident. Finally, the expression of proinflammatory cytokines was detected (weeks 12 to 14). In summary, (1) chemokines are upregulated before inflammatory cell infiltration, proteinuria, and kidney damage are observed; (2) chemokine generation is restricted to sites of subsequent inflammatory cell infiltration, i.e., glomeruli and interstitium; (3) chemokine receptor expression parallels mononuclear cell infiltration; and (4) proinflammatory cytokines are upregulated later, in parallel with inflammatory cell infiltration and the onset of proteinuria. These results support the hypothesis that chemokines initiate leukocyte infiltration and precede proteinuria and renal damage in MRL/lpr mice.