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CX 3 CR1 modulates SLE-associated glomerulonephritis and cardiovascular disease in MRL/lpr mice.
- Source :
-
Inflammation research : official journal of the European Histamine Research Society ... [et al.] [Inflamm Res] 2023 May; Vol. 72 (5), pp. 1083-1097. Date of Electronic Publication: 2023 Apr 15. - Publication Year :
- 2023
-
Abstract
- 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 <subscript>3</subscript> CR1.<br />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 <subscript>3</subscript> 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.<br />Results: Cx3cr1 <superscript>-/-</superscript> MRL/lpr mice exhibited a distinct phenotype of exacerbated glomerulonephritis compared to Cx3cr1 <superscript>+/+</superscript> 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 <subscript>3</subscript> CR1 controls glomerulonephritis in MRL/lpr mice through a gut microbiota-dependent mechanism. Upon treatment with HFD, Cx3cr1 <superscript>-/-</superscript> MRL/lpr mice developed significantly more atherosclerotic plaques that were promoted by Ly6C <superscript>+</superscript> 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 <superscript>+</superscript> monocytes and their display of ICOS-L.<br />Conclusions: We uncovered novel, Cx3cr1 deficiency-mediated pathogenic mechanisms contributing to SLE-associated glomerulonephritis and cardiovascular disease.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Details
- Language :
- English
- ISSN :
- 1420-908X
- Volume :
- 72
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Inflammation research : official journal of the European Histamine Research Society ... [et al.]
- Publication Type :
- Academic Journal
- Accession number :
- 37060359
- Full Text :
- https://doi.org/10.1007/s00011-023-01731-1