Abstract
Systemic lupus erythematosus (SLE) patients have increased prevalence of metabolic syndrome but the underlying mechanisms are unknown. Toll-like receptor 7 (TLR7) that detects single stranded-RNA plays a key role in antimicrobial host defense and also contributes to the initiation and progression of SLE both in mice and humans. Here, we report the implication of TLR7 signaling in high fat diet (HFD)-induced metabolic syndrome and exacerbation of lupus autoimmunity in TLR8-deficient (TLR8ko) mice, which develop spontaneous lupus-like disease due to increased TLR7 signaling by dendritic cells (DCs). The aggravated SLE pathogenesis in HFD-fed TLR8ko mice was characterized by increased overall immune activation, anti-DNA autoantibody production, and IgG/IgM glomerular deposition that were coupled with increased kidney histopathology. Moreover, upon HFD TLR8ko mice developed metabolic abnormalities, including liver inflammation. In contrast, upon HFD TLR7/8ko mice did not develop SLE and both TLR7ko and TLR7/8ko mice were fully protected from metabolic abnormalities, including body weight gain, insulin resistance, and liver inflammation. Interestingly, HFD led to an increase of TLR7 expression in WT mice, that was coupled with increased TNF production by DCs, and this phenotype was more profound in TLR8ko mice. Our study uncovers the implication of TLR7 signaling in the interconnection of SLE and metabolic abnormalities, indicating that TLR7 might be a novel approach as a tailored therapy in SLE and metabolic diseases.
Highlights
Epidemiological data provide evidence of a significant increase of autoimmune diseases in the last 30 years and growing attention has focused on the role of environmental factors, especially the western dietary habits that have led to the parallel rise in obesity [1]
Using TLR8ko mice on the C57BL/6 background that develop lupus due to increased Toll-like receptor 7 (TLR7) expression and signaling by dendritic cells [26, 28], our data clearly demonstrate that high fat diet (HFD) leads to exacerbation of lupus autoimmunity and metabolic parameters and these phenomena could be attributed to increased TLR7 expression and signaling (Figure 7)
We demonstrated that HFD-induced obesity aggravated the severity of lupus in TLR8ko female mice
Summary
Epidemiological data provide evidence of a significant increase of autoimmune diseases in the last 30 years and growing attention has focused on the role of environmental factors, especially the western dietary habits that have led to the parallel rise in obesity [1]. A link between obesity, metabolic syndrome and autoimmune diseases, including systemic lupus erythematosus (SLE), and the associated chronic inflammation has been suggested, but the underlying mechanisms are still unknown [2, 3]. SLE is a chronic systemic autoimmune disease predominantly affecting young women, during their reproductive years, and is characterized by the presence of autoantibodies against selfnucleic acids and associated proteins [4]. Not all patients respond to these treatments, and one major side effect of the systemic immunosuppression is the increased incidence of infection [5]. Better understanding of the pathogenesis of SLE is pivotal for the development of new treatments
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