BCG component mycolic acid protects against monocyte exhaustion in vitro

Abstract Monocyte exhaustion reflected in pathogenic inflammation and immune suppression underlies the pathogenesis of sepsis. The objective of this study is to define novel approaches in alleviating monocyte exhaustion, based on intriguing clinical reports that BCG components may be beneficial in reducing polymicrobial infection-triggered sepsis severity. We recapitulated in vitrothe development of exhausted murine monocytes through prolonged culture with high dose bacterial lipopolysaccharide (LPS), measured by the expansion of immature Ly6C hipopulation with elevated expression of pathogenic mediator CD38 and immune suppressor PD-L1, and reduced expression of CD86. Intriguingly, we observed that co-culture of murine bone marrow monocytes with Mycobacterium tuberculosis(BCG) component mycolic acid (MA) can significantly alleviate the development of exhausted monocytes. We found that monocytes co-stimulated with MA and LPS exhibited significantly reduced induction of CD38 and PD-L1 as compared to monocytes challenged with LPS alone. On the other hand, monocytes co-treated with MA and LPS exhibited enhanced expression of CD86 as compared to cells treated with LPS. In the monocyte-T cell coculture system, we found that T cells co-cultured with MA and LPS-treated monocytes had a significantly higher proliferation potential as compared to the T cells co-cultured with LPS-treated monocytes. Mechanically, we demonstrated that MA exerts its protective effect by selectively activating P-AKT and inhibiting STAT1/P-STAT1. In conclusion, we demonstrate that the BCG component mycolic acid can potently alleviate monocyte exhaustion and may serve as a future promising agent in treating sepsis. Supported by grants from NIH (AI136386)