Inhibition of Mitochondrial Succinate Dehydrogenase with Dimethyl Malonate Promotes M2 Macrophage Polarization by Enhancing STAT6 Activation.

Macrophages exhibit diverse phenotypes depending on environment status, which contribute to physiological and pathological processes of immunological diseases, including sepsis, asthma, multiple sclerosis and colitis. The alternative activation of macrophages is tightly regulated to avoid excessive activation and damage of tissues and organs. Certain works characterized that succinate dehydrogenase (SDH) altered function of macrophages and promoted inflammatory response in M1 macrophages via mitochondrial reactive oxygen species (ROS). However, the effect of succinate dehydrogenase on M2 macrophage polarization remains incompletely understood. We employed dimethyl malonate (DMM) to inhibit succinate dehydrogenase activity and took use of RNA-seq to analyze the changes of inflammatory response of LPS-activated M1 macrophages or IL 4-activated M2 macrophages. Our data revealed that inhibition of SDH with DMM increased expression of M2 macrophages-associated signature genes, including Arg1, Ym1 and Mrc1. Consistent with previous work, we also observed that inhibition of SDH decreased the expression of IL-1β and enhanced the levels of IL-10 in M1 macrophages. Additionally, inhibition of SDH with DMM inhibited the production of chemokines, such as Cxcl3, Cxcl12, Ccl20 and Ccl9. DMM also amplified the M2 macrophages-related signature genes in IL-13-activated M2 macrophages. Mechanistic studies revealed that DMM promoted M2 macrophages polarization through mitochondrial ROS dependent STAT6 activation. Blocking ROS with mitoTEMPO or inhibiting STAT6 activation with ruxolitinib abrogated the promotion effect of DMM on M2 macrophages. Finally, dimethyl malonate treatment promoted peritoneal M2 macrophages differentiation and exacerbated OVA-induced allergy asthma in vivo. Collectively, we identified SDH as a braker to suppress M2 macrophage polarization via mitochondrial ROS, suggesting a novel strategy to treatment of M2 macrophages-mediated inflammatory diseases.