RESUMEN
Hyper-activations of monocytes/macrophages and dendritic cells (DCs) contribute to the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus (SLE). Fatty acid synthase (FASN) is essential for the de novo synthesis of long-chain fatty acids, which play a key role in controlling the activation, differentiation, and function of immune cells. However, the role of FASN in regulating the activations of monocytes/macrophages and DCs has not been studied. In this study, we investigated the involvement of the FASN in modulating the activations of macrophages and DCs, as well as the pathogenesis of SLE. Importantly, we observed a significant upregulation of FASN expression in monocytes and DCs from patients with SLE. This increase is strongly correlated with disease severity and activation status of the immune cells. Furthermore, overexpression of FASN significantly boosts the TLR4/7/9-mediated activation of macrophages and DCs, while knockdown of FASN markedly inhibits this activation. Notably, knockdown of FASN alleviates TLR7 agonist imiquimod (IMQ)-induced lupus in mice and the activation of macrophages and DCs. It makes more sense that pharmaceutical targeting of FASN by using TVB-2640 significantly alleviates IMQ-induced lupus in mice and the activation of macrophages and DCs, as well as in spontaneous lupus MRL/lpr mice. Thus, FASN contributes to the TLRs-mediated activation of macrophages and DCs, as well as the pathogenesis of SLE. More importantly, FASN inhibitor TVB-2640 is expected to be an effective drug in the treatment of SLE.
RESUMEN
The interleukin 17 (IL-17) family of cytokines has emerged as a critical player in autoimmune disease, including systemic lupus erythematosus (SLE). However, the role of IL-17B, a poorly understood cytokine, in the pathogenesis of SLE is still not known. In this study, we investigated the role of IL-17B in the activation and differentiation of B cells, and the pathogenesis of SLE. Intriguingly, IL-17B deficiency aggravated disease in lupus-prone mice and promoted the activation of B cells and the differentiation of germinal center B cells and plasma cells, while recombinant mouse IL-17B (rmIL-17B) significantly alleviated disease in lupus-prone mice. Mechanistically, rmIL-17B inhibited the activation of the Toll-like receptor and interferon pathways in B cells by downregulating fatty acid synthase-mediated (FASN-mediated) lipid metabolism. Loss of FASN significantly alleviated the disease in lupus-prone mice and inhibited the activation and differentiation of B cells. In addition, B cells had greater FASN expression and lower IL-17RB levels in patients with SLE than in healthy controls. Our study describes the role of IL-17B in regulating B cell activation and differentiation, and alleviating the onset of SLE. These findings will lay a theoretical foundation for further understanding of the pathogenesis of SLE.
RESUMEN
Toll-like receptors (TLRs), especially TLR7, play an important role in systemic lupus erythematosus (SLE) pathogenesis. However, the regulatory mechanism underlying the abnormal activation of TLR pathways in patients with SLE has not been elucidated. Notably, accumulating evidence indicates that myeloid-derived suppressor cells (MDSCs) are important regulators of inflammation and autoimmune diseases. Compared with healthy control subjects, patients with SLE have a greater proportion of MDSCs among peripheral blood mononuclear cells (PBMCs); however, the effect of MDSCs on TLR7 pathway activation has not been determined. In the present study, lupus MDSCs significantly promoted TLR7 pathway activation in macrophages and dendritic cells (DCs), exacerbating the imiquimod-induced lupus model. RNA-sequencing analysis revealed significant overexpression of S100 calcium-binding protein A8 (S100A8) and S100A9 in MDSCs from diseased MRL/lpr mice. In vitro and in vivo studies demonstrated that S100A8/9 effectively promoted TLR7 pathway activation and that S100A8/9 deficiency reversed the promoting effect of MDSCs on TLR7 pathway activation in lupus. Mechanistically, MDSC-derived S100A8/9 upregulated interferon gamma (IFN-γ) secretion by macrophages and IFN-γ subsequently promoted TLR7 pathway activation in an autocrine manner. Taken together, these findings suggest that lupus MDSCs promote TLR7 pathway activation and lupus pathogenesis through the S100A8/9-IFN-γ axis. Our study identified an important target for SLE therapy.
