Lack of chemokine receptor CCR1 enhances Th1 responses and glomerular injury during nephrotoxic nephritis
Peter S. Topham, … , David J. Salant, Wayne W. Hancock
Peter S. Topham, … , David J. Salant, Wayne W. Hancock
Published December 1, 1999
Citation Information: J Clin Invest. 1999;104(11):1549-1557. https://doi.org/10.1172/JCI7707.
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Article

Lack of chemokine receptor CCR1 enhances Th1 responses and glomerular injury during nephrotoxic nephritis

Abstract

During the development of nephrotoxic nephritis (NTN) in the mouse, we find that a variety of chemokines and chemokine receptors are induced: CCR1 (RANTES, MIP-1α), CCR2 (MCP-1), CCR5 (RANTES, MIP-1α, MIP-1β), CXCR2 (MIP-2), and CXCR3 (IP-10). Their timing of expression indicated that CXCR2 and CCR1 are probably important in the neutrophil-dependent heterologous phase of the disease, whereas CCR1, CCR2, CCR5, and CXCR3 accompany the subsequent mononuclear cell infiltration characteristic of autologous disease. We therefore assessed the role of CCR1 in NTN using CCR1–/– mice. We found that neutrophil accumulation in CCR1–/– mice was comparable to that in wild-type animals but that renal recruitment of CD4+ and CD8+ T cells and macrophages increased significantly. Moreover, CCR1–/– mice developed more severe glomerulonephritis than did controls, with greater proteinuria and blood urea nitrogen, as well as a higher frequency of crescent formation. In addition, CCR1–/– mice showed enhanced Th1 immune responses, including titers of antigen-specific IgG2a antibody, delayed-type hypersensitivity responses, and production of IFN-γ and TNF-α. Lastly, using recombinant proteins and transfected cells that overexpressed CCR1, we demonstrated that MIP-1α, but not RANTES, bound CCR1 and induced cell chemotaxis. Thus, rather than simply promoting leukocyte recruitment during NTN, CCR1 expression profoundly alters the effector phase of glomerulonephritis. Therapeutic targeting of chemokine receptors may, on occasion, exacerbate underlying disease.

Authors

Peter S. Topham, Vilmos Csizmadia, Dulce Soler, Dawn Hines, Craig J. Gerard, David J. Salant, Wayne W. Hancock

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CCR1–/– mice show greater histologic injury than do CCR1+/+ mice, as ref...
CCR1–/– mice show greater histologic injury than do CCR1+/+ mice, as reflected by quantitative assessment of (a) numbers of glomerular cells, crescent formation, glomerulosclerosis, and (b) T-cell and (c) macrophage accumulation in nephritic CCR1+/+ mice (open bars) vs. nephritic CCR1–/– mice (solid bars) and normal CCR1+/+ mice (gray bars). Assessment (as detailed in Methods) was performed 21 days after NTS injection, using 8 mice per group; results of analysis by Student’s t test are presented as mean ± SD. *P < 0.05; **P < 0.01 for nephritic CCR1–/– mice vs. nephritic CCR1+/+ mice. (d and e) Representative histopathology of kidneys (8/group) harvested at day 21 after NTS from CCR1–/– and CCR1+/+ mice. (d) In CCR1–/– mice, most glomeruli showed extensive glomerulosclerosis and crescent formation (arrows), whereas CCR+/+ mice (e) typically showed considerably less glomerulosclerosis (arrows) and infrequent crescent formation. Paraffin sections, periodic acid–Schiff reagent counterstain, ×400.