Mannose receptor interacts with Fc receptors and is critical for the development of crescentic glomerulonephritis in mice
Konstantia-Maria Chavele, Luisa Martinez-Pomares, Jan Domin, Samantha Pemberton, Stuart M. Haslam, Anne Dell, H. Terence Cook, Charles D. Pusey, Siamon Gordon, Alan D. Salama
Konstantia-Maria Chavele, Luisa Martinez-Pomares, Jan Domin, Samantha Pemberton, Stuart M. Haslam, Anne Dell, H. Terence Cook, Charles D. Pusey, Siamon Gordon, Alan D. Salama
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Research Article Nephrology

Mannose receptor interacts with Fc receptors and is critical for the development of crescentic glomerulonephritis in mice

Abstract

Crescentic glomerulonephritis (CGN), which frequently results in acute and chronic kidney disease, is characterized by and dependent on glomerular infiltration by macrophages. The mannose receptor (MR) is a pattern recognition receptor implicated in the uptake of endogenous and microbial ligands by macrophages, mesangial cells (MCs), and selected endothelial cells. It is upregulated on alternatively activated macrophages (i.e., macrophages associated with tissue repair and humoral immunity) and involved in antigen presentation to T cells. We used the mouse model of nephrotoxic nephritis to investigate the role of MR in CGN. Our results demonstrate what we believe to be a novel role for MR in the promotion of CGN that is independent of adaptive immune responses. MR-deficient (Mr–/–) mice were protected from CGN despite generating humoral and T cell responses similar to those of WT mice, but they demonstrated diminished macrophage and MC Fc receptor–mediated (FcR-mediated) functions, including phagocytosis and Fc-mediated oxygen burst activity. Mr–/– MCs demonstrated augmented apoptosis compared with WT cells, and this was associated with diminished Akt phosphorylation. Macrophage interaction with apoptotic MCs induced a noninflammatory phenotype that was more marked in Mr–/– macrophages than in WT macrophages. Our results demonstrate that MR augments Fc-mediated function and promotes MC survival. We suggest that targeting MR may provide an alternative therapeutic approach in CGN while minimizing the impact on adaptive immune responses, which are affected by conventional immunosuppressive approaches.

Authors

Konstantia-Maria Chavele, Luisa Martinez-Pomares, Jan Domin, Samantha Pemberton, Stuart M. Haslam, Anne Dell, H. Terence Cook, Charles D. Pusey, Siamon Gordon, Alan D. Salama

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Figure 5

MR deficiency induces augmented MC proliferation and apoptosis.

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MR deficiency induces augmented MC proliferation and apoptosis. (A) Quan...
(A) Quantification of spontaneous MC proliferation by overnight tritiated thymidine incorporation. Mr–/– cells displayed significantly greater rates of proliferation (in cpm) than did their WT counterparts. (B) Rates of apoptosis of cultured MCs, measured by annexin V+ FACS staining, were significantly higher in Mr–/– cells. (C) p-Akt and total Akt protein expression was assessed by Western blot in WT and Mr–/– MC lysates at basal levels and after stimulation with 10% FCS. (D) Densitometry of the bands showed that basal levels were lower in Mr–/– cells and did not increase after exposure to 10% FCS, as they did in WT cells. (E) Increased MC apoptosis was found in vivo in Mr–/– mice with NTN. The number of TUNEL+ cells in glomeruli from kidneys of WT and Mr–/– animals at day 8 was scored and demonstrated significantly higher counts in Mr–/– than WT mice. *P < 0.05; **P < 0.01.