Male microbiota-associated metabolites restore macrophage efferocytosis in female lupus-prone mice via PPARγ and LXR signaling pathways

Abstract

Abstract Sex and gut microbiota both influence systemic lupus erythematosus (SLE) development. We have found that male and lupus-prone female NZBxNZW F1 (BWF1) mice exhibit differences in gut microbiota and metabolomic profiles, and transfer of male microbiota suppresses disease in female mice. Here we determine how sex and microbiota may interact to affect SLE development. Transcriptomic analysis of female and male BWF1 spleens found phagocytosis-promoting genes were upregulated in males. Since defects in macrophage-mediated phagocytosis of apoptotic cells (efferocytosis) are found in SLE patients, we compared efferocytosis in vitro between male and lupus-prone female BWF1 mice. Macrophage-mediated efferocytosis was decreased in female compared to male BWF1 mice, but could be restored in female mice by transfer of male microbiota in vivo. Further transcriptomic analysis of spleens found that genes regulated by PPARγ and LXR receptor signaling were increased in male BWF1 mice. Our previous metabolomics analyses have found that two metabolites which can activate PPARγ and LXR signaling, phytol and its derivative phytanic acid, are higher in male BWF1 mice. We have also found that feeding phytanic acid to female mice delayed lupus onset. We show here that defective female BWF1 macrophage efferocytosis can be restored by phytanic acid treatment, and this requires both PPARγ and LXR signaling pathways. Furthermore, we found that phytanic acid may restore female BWF1 macrophage efferocytosis by upregulating the pro-efferocytic receptor, CD36. Taken together, our data indicate that BWF1 male microbiota produce metabolites that can enhance macrophage efferocytosis and suppress lupus.