Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

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 À/À 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 1 , CD8 1 , CD11c 1 and alpha smooth muscle actin (aSMA) 1 cells were reduced in allografts from Ccr5 À/À 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 a, mannose receptor, C type 1), were strongly upregulated (mRNA and/or protein level) only in allografts from Ccr5 À/À 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 À/À 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.

Macrophage Phenotype Controls Long-Term AKI Outcomes—Kidney Regeneration versus Atrophy

“…This, in turn, implies that immunoregulatory macrophages are needed for recovery, and their association with renal fibrosis rather indicates their insufficient capacity to always promote sufficient epithelial repair, a concept supported by studies from several other groups. [20][21][22]45,46,54 We conclude that IRAK-M deficiency is sufficient to turn AKI recovery into progressive CKD, because IRAK-M is needed to suppress persistent macrophage-related renal inflammation. This implies the following: (1) kidney regeneration first requires the resolution of renal inflammation; (2) resolution of kidney inflammation is an active, not passive, process; (3) alternatively activated mononuclear phagocytes support epithelial regeneration; (4) kidney shrinkage in CKD upon AKI mostly results from the loss of tubules; (5) genetic and environmental factors can negatively affect long-term outcomes of AKI by modulating renal mononuclear phagocyte activation state; and (6) IRAK-M contributes to tissue regeneration.…”

Protective role for CCR5 in murine lupus nephritis

“…However, none of the potential mechanisms that have been described in the literature, including reduced infiltration of alternatively activated macrophages (3,11), alterations in T effector cell balance, interference with the humoral immune response (2), or a defect in apoptosis (43) were detectable in the CCR5 Ϫ/Ϫ MRL/lpr mice. Furthermore, in contrast to previous reports on dermal Leishmania infection (45), we could not detect impaired tissue infiltration of Tregs in the CCR5 Ϫ/Ϫ MRL/lpr mice.…”

“…Since CCR5 has been described to influence monocyte migration in a subtype-specific way (11,36), in a next step we aimed to characterize the infiltration of cells derived from the myeloid lineage in more detail. Immunohistochemistry for the marker F4/80 with subsequent quantification of tubulointerstitial F4/ 80 ϩ cells showed a significant increase in CCR5 Ϫ/Ϫ MRL/lpr mice compared with their wild-type littermates ( Fig.…”

Inflammation-mediated promotion of invasion and metastasis

“…CCR5 deficiency also favors M2 polarization [36]. CCL2 has been demonstrated to play a role not only in attracting tumor-promoting macrophages in carcinoma of the prostate but also in supporting their survival and M2 polarization [37].…”