α-KETOGLUTARATE MODULATES MACROPHAGE POLARIZATION THROUGH REGULATION OF PPARγ TRANSCRIPTION AND MTORC1/P70S6K PATHWAY TO AMELIORATE ALI/ARDS

As tissue-resident cells in the lung, alveolar macrophages display remarkable heterogeneity and play a crucial role in the development and control of septic acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Recent evidence suggests that alpha-ketoglutarate (alpha-KG) plays an important role in alternative activation of macrophage (M2) through metabolic and epigenetic reprogramming, and thus possesses anti-inflammatory properties. However, the underlying mechanisms of alpha-KG's effect on alveolar macrophage polarization and the potential effects of alpha-KG in ALI/ARDS remain unclear. Here, we examined the effects and mechanisms of alpha-KG on alveolar macrophage polarization, and investigated the possible effects of alpha-KG on lipopolysaccharide (LPS)-induced ALI/ARDS in a mouse model. We found that alpha-KG inhibited M1 macrophage polarization and promoted IL-4-induced M2 macrophage polarization in MH-S cells (a murine alveolar macrophage cell line). Further experiments showed that alpha-KG down-regulated the expression of M1-polarized marker genes and inhibited the activities of mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal protein S6 kinase (p70S6K) signaling pathway in M1-polarized MH-S cells. Moreover, our results showed that alpha-KG promoted IL-4-induced M2 polarization of MH-S cells by augmenting nuclear translocation of peroxisome proliferator-activated receptor gamma (PPAR gamma) and increasing expression of relevant fatty acid metabolic genes. Finally, using an LPS-induced ALI/ARDS mouse model, we found that alpha-KG ameliorated the LPS-induced inflammation and lung pathological damage, as well as alpha-KG pretreated mice had better clinical scores compared with the LPS group. These findings reveal new mechanisms of alpha-KG in regulating macrophage polarization which may provide novel strategies for the prevention and treatment of inflammatory diseases, including sepsis and septic ALI/ARDS.