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Updated: Jun 19, 2026
Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity
Published on: June 7, 2017
Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long-term renal allograft
Stefan Dehmel1, Shijun Wang, Claudia Schmidt
1Klinikum der Universität München, Medizinische Poliklinik-Innenstadt, München, Germany.
Abstract:
The chemokine (C-C motif) receptor 5 (CCR5) has been implicated in experimental and clinical allograft rejection. To dissect the function of CCR5 in acute and chronic renal allograft rejection, bilaterally nephrectomized WT and Ccr5-/- C57BL/6 mice were used as recipients of WT BALB/c renal allografts and analyzed 7 and 42 days after transplantation. Lesion scores (glomerular damage, vascular rejection, tubulointerstitial inflammation) and numbers of CD4+, CD8+, CD11c+ and alpha smooth muscle actin (alphaSMA)+ cells were reduced in allografts from Ccr5-/- recipients during the chronic phase. Increasing creatinine levels indicated deterioration of allograft function over time. While mRNA expression of Th1-associated markers decreased between 7 and 42 days, Th2-associated markers increased. Markers for alternatively activated macrophages (arginase 1, chitinase 3-like 3, resistin-like alpha, mannose receptor, C type 1), were strongly upregulated (mRNA and/or protein level) only in allografts from Ccr5-/- recipients at 42 days. Ccr5 deficiency shifted intragraft immune responses during the chronic phase towards the Th2 type and led to accumulation of alternatively activated macrophages. Additionally, splenocytes from unchallenged Ccr5-/- mice showed significantly increased arginase 1 and mannose receptor 1 mRNA levels, suggesting constitutive alternative activation of splenic macrophages. We conclude that Ccr5 deficiency favors alternative macrophage activation. This finding may be relevant for other inflammatory diseases that involve macrophage activation and may also influence future therapeutic strategies targeting CCR5.
Insights
Chemokine receptor 5 (CCR5) deficiency reduces kidney allograft rejection by promoting alternative macrophage activation. This CCR5 role impacts immune responses and may inform future therapies for inflammatory diseases.
Area of Science:
- Immunology
- Transplantation Biology
- Renal Medicine
Background:
- Chemokine (C-C motif) receptor 5 (CCR5) plays a role in allograft rejection.
- Understanding CCR5's function in renal transplantation is crucial for improving outcomes.
Purpose of the Study:
- To investigate the specific role of CCR5 in acute and chronic renal allograft rejection.
- To analyze the impact of CCR5 deficiency on immune cell infiltration and macrophage activation in kidney allografts.
Main Methods:
- Used bilaterally nephrectomized WT and Ccr5-/- mice as recipients of WT BALB/c renal allografts.
- Assessed allograft function, histological lesion scores, and immune cell populations (CD4+, CD8+, CD11c+, alphaSMA+) at 7 and 42 days post-transplantation.
- Quantified mRNA and protein levels of Th1/Th2 markers and alternatively activated macrophage markers (arginase 1, chitinase 3-like 3, etc.).
Main Results:
- Ccr5-/- recipients showed reduced lesion scores and immune cell infiltration in chronic allograft rejection.
- Allograft function deteriorated over time, indicated by increasing creatinine levels.
- CCR5 deficiency promoted a shift towards Th2 immune responses and increased alternatively activated macrophages in chronic allografts.
- Splenocytes from Ccr5-/- mice exhibited constitutive alternative macrophage activation.
Conclusions:
- CCR5 deficiency favors alternative macrophage activation, shifting intragraft immune responses towards a Th2 type during chronic renal allograft rejection.
- These findings suggest CCR5's critical role in regulating immune responses during transplantation.
- The study highlights potential therapeutic strategies targeting CCR5 for inflammatory diseases involving macrophage activation.
