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CX3CR1 modulates SLE-associated glomerulonephritis and cardiovascular disease in MRL/lpr mice
Xavier Cabana-Puig1, Ran Lu1,2, Shuo Geng2
1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA.
Insights
Systemic lupus erythematosus (SLE) complications, like kidney and heart disease, are worsened by CX3CR1 deficiency. Gut microbiota modulation and CX3CR1 signaling impact SLE pathogenesis.
Area of Science:
- Immunology
- Microbiology
- Genetics
Background:
- Systemic lupus erythematosus (SLE) is an autoimmune disease causing multi-organ damage, including kidney and heart complications.
- The chemokine receptor CX3CR1's role in SLE pathogenesis remains incompletely understood.
- Understanding CX3CR1's mechanisms is crucial for developing targeted therapies for SLE-associated organ damage.
Purpose of the Study:
- To investigate the role of CX3CR1 in the development of glomerulonephritis and cardiovascular disease in a lupus-prone mouse model.
- To elucidate the mechanisms by which CX3CR1 deficiency influences SLE pathogenesis, focusing on immune cell populations and gut microbiota interactions.
- To assess the impact of CX3CR1 deficiency on atherosclerosis development and autoantibody production.
Main Methods:
- Generated Cx3cr1-deficient MRL/lpr lupus-prone mice via backcrossing and heterozygous intercross.
- Administered Lactobacillus spp. to assess gut microbiota's role and high-fat diet (HFD) to evaluate cardiovascular impact.
- Analyzed kidney and heart tissues, immune cell populations (e.g., marginal zone macrophages, T cells, monocytes), and autoantibody production.
Main Results:
- Cx3cr1 deficiency exacerbated glomerulonephritis, linked to reduced splenic tolerogenic macrophages and increased double-negative T cells.
- Lactobacillus administration reversed glomerulonephritis, indicating a gut microbiota-dependent mechanism controlled by CX3CR1.
- Cx3cr1 deficiency promoted HFD-induced atherosclerosis via Ly6C+ monocyte activation, ICOS-L/ICOS interaction, and autoantibody production, creating a positive feedback loop.
Conclusions:
- CX3CR1 deficiency exacerbates SLE-associated glomerulonephritis through gut microbiota-dependent pathways.
- CX3CR1 deficiency promotes atherosclerosis in SLE by enhancing monocyte-driven inflammation and autoantibody production.
- These findings reveal novel CX3CR1-mediated pathogenic mechanisms contributing to multi-organ damage in SLE.
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 CX3CR1.
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 CX3CR1. 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 CX3CR1 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.
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