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Glomerular expression of C-C chemokines in different types of human crescentic glomerulonephritis
Zhi-Hong Liu1, Shu-Fen Chen, Hong Zhou
1Research Institute of Nephrology, Nanjing University School of Medicine, Jinling Hospital, Nanjing, PR China. zhihong@public1.ptt.js.cn
Insights
C-C chemokines like MCP-1 and MIP-1alpha are key drivers of macrophage recruitment in crescentic glomerulonephritis (CGN), particularly in cellular crescents and type I CGN, influencing fibrosis and prognosis.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Crescentic glomerulonephritis (CGN) is a rapidly progressive kidney disease where macrophages are central to pathogenesis.
- The exact molecular mechanisms of macrophage recruitment and activation in CGN remain unclear.
- C-C chemokines, including monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha and beta (MIP-1alpha/beta), are critical for macrophage attraction.
Purpose of the Study:
- To investigate the expression of C-C chemokines (MCP-1, MIP-1alpha, MIP-1beta) in human CGN.
- To correlate chemokine expression with CD68-positive macrophages in different CGN types.
- To understand the role of these chemokines in crescent formation and fibrotic progression.
Main Methods:
- Immunohistochemistry was used to detect MCP-1, MIP-1alpha, MIP-1beta, and CD68 in renal biopsies from 32 CGN patients and 8 controls.
- Biopsies included anti-GBM disease (type I), immune complex (type II), and pauci-immune (type III) CGN.
- Analysis focused on cellular, fibrocellular, and fibrous crescents.
Main Results:
- Chemokines and CD68 were absent in normal kidneys but present in cellular and fibrocellular crescents of CGN patients.
- Infiltrating macrophages (CD68-positive) expressed MCP-1, MIP-1alpha, and MIP-1beta, correlating positively with CD68 counts.
- Type I CGN showed higher MCP-1/MIP-1alpha expression and Bowman's capsule rupture incidence compared to types II and III.
Conclusions:
- Expressed C-C chemokines likely mediate inflammation, crescent formation, and fibrosis in CGN.
- MCP-1 and MIP-1alpha are crucial for macrophage recruitment in cellular crescents.
- Elevated MCP-1 and MIP-1alpha in type I CGN suggest a role in its severe course and poorer prognosis.
Background:
Crescentic glomerulonephritis (CGN) presents a rapidly progressive glomerulonephritis clinically, in which macrophages play a crucial role in the pathogenesis. However, the precise molecular mechanism of macrophage recruitment and activation has not been fully elucidated. C-C chemokines, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha and beta (MIP-1alpha and MIP-1beta), are major chemoattractants for macrophages. We attempted to study the expression of C-C chemokines and their correlation with CD68-positive macrophages in crescentic glomeruli to investigate further their possible roles in crescent formation and progression to fibrosis in different types of human CGN.
Methods:
The expression of MCP-1, MIP-1alpha, MIP-1beta and CD68 was detected in glomeruli with different forms of crescents (cellular, fibrocellular and fibrous crescents) by immunohistochemistry in serial sections of renal biopsies taken from 32 patients with biopsy-proven CGN including eight patients with anti-glomerular basement membrane (GBM) disease (type I CGN), 12 patients with immune complex-mediated CGN (type II CGN) and another 12 patients with pauci-immune CGN (type III CGN) enrolled in this study. Eight normal human kidneys were obtained from cadaveric renal transplant donors whose kidneys were technically unsuitable for transplantation, serving as controls.
Results:
MCP-1, MIP-1alpha, MIP-1beta and CD68 were undetectable in glomeruli of normal kidney. In crescentic biopsies, MCP-1, MIP-1alpha, MIP-1beta and CD68 were detected in fibrocellular crescents and were even more prominent in cellular crescents, but were undetectable in fibrous crescents. Using consecutive sections for staining, it was demonstrated that a high proportion of infiltrating CD68-positive macrophages, mainly localized to the area of the expression of chemokines, were MCP-1, MIP-1alpha and MIP-1beta positive in crescents. Chemokines were expressed mainly by CD68-positive macrophages and parietal epithelial cells in crescents. The number of MCP-1- and MIP-1alpha-positive cells in glomeruli with cellular crescents was positively correlated with the number of CD68-positive cells (r = 0.568 and 0.749, respectively, both P < 0.01). The number of MCP-1- and MIP-1alpha-positive cells and the incidence of Bowman's capsule rupture in glomeruli of patients with type I CGN were higher than those of type II and type III CGN.
Conclusions:
These observations suggest that the expressed C-C chemokines, MCP-1, MIP-1alpha and MIP-1beta, may mediate the inflammatory process of crescent formation and progression to fibrosis. The strong correlation of MCP-1 and MIP-1alpha with infiltrating macrophages within glomeruli with cellular crescents suggested that these chemokines might be of particular importance for macrophage recruitment to this site. MCP-1 and MIP-1alpha were correlated to type I CGN with its more severe inflammatory course and worse prognosis. The variance of glomerular expression of C-C chemokines may contribute to the difference in histopathological features and prognosis in these three types of CGN.