Chemokine Receptor Ccr2 Deficiency Reduces Renal Disease and Prolongs Survival in MRL/lpr Lupus-Prone Mice

Abstract

MRL/MpJ-Faslpr /J (MRL/lpr) mice represent a well-established mouse model of human systemic lupus erythematosus. MRL/lpr mice homozygous for the spontaneous lymphoproliferation mutation (lpr) are characterized by systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, splenomegaly, hypergammaglobulinemia, arthritis, and fatal immune complex-mediated glomerulonephritis. It was reported previously that steady-state mRNA levels for the chemokine (C-C motif) receptor 2 (Ccr2) continuously increase in kidneys of MRL/lpr mice. For examining the role of Ccr2 for development and progression of immune complex-mediated glomerulonephritis, Ccr2-deficient mice were generated and backcrossed onto the MRL/lpr genetic background. Ccr2-deficient MRL/lpr mice developed less lymphadenopathy, had less proteinuria, had reduced lesion scores, and had less infiltration by T cells and macrophages in the glomerular and tubulointerstitial compartment. Ccr2-deficient MRL/lpr mice survived significantly longer than MRL/lpr wild-type mice despite similar levels of circulating immunoglobulins and comparable immune complex depositions in the glomeruli of both groups. Anti-dsDNA antibody levels, however, were reduced in the absence of Ccr2. The frequency of CD8 ؉ T cells in peripheral blood was significantly lower in Ccr2-deficient MRL/lpr mice. Thus Ccr2 deficiency influenced not only monocyte/ macrophage and T cell infiltration in the kidney but also the systemic T cell response in MRL/lpr mice. These data suggest an important role for Ccr2 both in the general development of autoimmunity and in the renal involvement of the lupus-like disease. These results identify Ccr2 as an additional possible target for the treatment of lupus nephritis.

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

“…Several published works have shown that CCR2 -/-mice are resistant to experimental autoimmune diseases, including the B cell-dominant lupus model [36,37]. These observations support our current findings and emphasize the importance of CCR2-CCL2 pathway in the development of autoimmunity.…”

The Pathogenesis of Lupus Nephritis

“…24 The members of the chemokine family specifically direct different leukocyte subsets by distinct chemokine receptors into different renal compartments. 63 For example, the chemokine CCL2 recruits CCR2 + proinflammatory macrophages and T cells into the glomerulus and the tubulointerstitium, 64,65 whereas CCR1 + cells only recruit to the interstitial compartment and not to the glomerulus in LN. 66 Other leukocyte subsets involve other chemokines and chemokine receptors for their recruitment into the kidney.…”

Involvement of CD11b+ GR-1low cells in autoimmune disorder in MRL-Fas lpr mouse

“…In this model, CCR2 has been reported to contribute to the progression of autoimmune kidney injury, followed by the decreased number of macrophage (Mφ) (14). However, the pathogenesis of MDSCs, especially focused on CCR2 signaling, remains to be investigated.…”