CX 3 CR1 modulates SLE-associated glomerulonephritis and cardiovascular disease in MRL/ lpr mice

Objective Patients with systemic lupus erythematosus (SLE) often develop multi-organ damages including heart and kidney complications. We sought to better define the underlying mechanisms with a focus on the chemokine receptor CX 3 CR1. Methods We generated Cx3cr1 -deficient MRL/ lpr lupus-prone mice through backcrossing. We then employed heterozygous intercross to generate MRL/ lpr littermates that were either sufficient or deficient of CX 3 CR1. The mice were also treated with either Lactobacillus spp. or a high-fat diet (HFD) followed by assessments of the kidney and heart, respectively. Results Cx3cr1 –/– MRL/ lpr mice exhibited a distinct phenotype of exacerbated glomerulonephritis compared to Cx3cr1 +/+ littermates, which was associated with a decrease of spleen tolerogenic marginal zone macrophages and an increase of double-negative T cells. Interestingly, upon correction of the gut microbiota with Lactobacillus administration, the phenotype of exacerbated glomerulonephritis was reversed, suggesting that CX 3 CR1 controls glomerulonephritis in MRL/ lpr mice through a gut microbiota-dependent mechanism. Upon treatment with HFD, Cx3cr1 –/– MRL/ lpr mice developed significantly more atherosclerotic plaques that were promoted by Ly6C + monocytes. Activated monocytes expressed ICOS-L that interacted with ICOS-expressing follicular T-helper cells, which in turn facilitated a germinal center reaction to produce more autoantibodies. Through a positive feedback mechanism, the increased circulatory autoantibodies further promoted the activation of Ly6C + monocytes and their display of ICOS-L. Conclusions We uncovered novel, Cx3cr1 deficiency-mediated pathogenic mechanisms contributing to SLE-associated glomerulonephritis and cardiovascular disease.