Chemokine expression precedes inflammatory cell infiltration and chemokinereceptor and cytokine expression during the initiation of murine lupus nephritis

Lupus nephritis is characterized by immune complex deposition and inflammat ory cell infiltration. Therefore, the initiation and progression of lupus n ephritis in MRL/MpJ Fas(lpr/lpr) (MRL/lpr) mice were investigated, with a f ocus on the expression of several chemokines and chemokine receptors. Mice were monitored for proteinuria from 6 to 20 wk of age, and kidneys were exa mined every 2 wk by light microscopy, electron microscopy, and immunohistol ogic analyses. Furthermore, the expression of chemokines, chemokine recepto rs, and proinflammatory cytokines was analyzed in ribonuclease protection a ssays. MRL/lpr mice demonstrated increased expression of monocyte chemoattr actant protein-1, regulated upon activation, normal T cell-expressed and -s ecreted protein, inducible protein of 10 kD, and macrophage inflammatory pr otein-1 beta at week 8. At that time point, levels of circulating and glome rular immune complexes were increased, and no proteinuria or histopathologi c signs of renal damage could be observed. As assessed in immunohistochemic al and in situ hybridization analyses, monocyte chemoattractant protein-1 a nd regulated upon activation, normal T cell-expressed and -secreted protein expression was preferentially located in the glomeruli and interstitium. M ononuclear 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 histologi cally evident. Finally, the expression of proinflammatory cytokines was det ected (weeks 12 to 14). In summary, (I) chemokines are upregulated before i nflammatory 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 recepto r expression parallels mononuclear cell infiltration; and (4) proinflammato ry cytokines are upregulated later, in parallel with inflammatory cell infi ltration and the onset of proteinuria. These results support the hypothesis that chemokines initiate leukocyte infiltration and precede proteinuria an d renal damage in MRL/lpr mice.