Hydroxychloroquine enhances efferocytosis and modulates the gut microbiome in mice with pristane-induced lupus

Background: An important contributor to the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE) is the impaired clearance of apoptotic cells (efferocytosis) and increasing evidence implicates microbiota dysbiosis as another important player. Hydroxychloroquine (HCQ) is frequently prescribed for the treatment of SLE. Here, we evaluate changes in efferocytosis and the gut microbiome in mice with pristane-induced lupus (PIL) by HCQ administration. Methods: PIL mice were studied with or without HCQ and/or resveratrol (RESV). Efferocytosis was determined in RAW 264.7 cells and peritoneal macrophages from mouse ascites fluid. The gut microbiome was analyzed using Illumina sequencing. Results: Both HCQ and RESV enhanced efferocytosis. HCQ also significantly suppressed ascites production of proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α). The Firmicutes / Bacteroidetes ( F/B ) ratio was significantly decreased in PIL mice compared with untreated controls (p<0.05). The F/B ratio in PIL mice was increased by HCQ alone and significantly increased by HCQ combined with RESV. Conclusions: In this study, HCQ and RESV enhanced efferocytosis in both RAW 264.7 cells and peritoneal macrophages of PIL mice. The pristane-induced reduction in the F/B ratio was restored by HCQ treatment. SLE treatment should consider the role of the gut microbiome.