Alleviation of monocyte exhaustion by BCG derivative mycolic acid

Monocyte exhaustion with sustained pathogenic inflammation and immune -suppression, a hallmark of sepsis resulting from systemic infections, presents a challenge with limited therapeutic solutions. This study identified Methoxy-Mycolic Acid (M -MA), a branched mycolic acid derived from Mycobacterium bovis Bacillus Calmette-Guerin (BCG), as a potent agent in alleviating monocyte exhaustion and restoring immune homeostasis. Co -treatment of monocytes with M -MA effectively blocked the expansion of Ly6Chi/CD38hi/PD-L1hi monocytes induced by LPS challenges and restored the expression of immuneenhancing CD86. M -MA treatment restored mitochondrial functions of exhausted monocytes and alleviated their suppressive activities on co -cultured T cells. Independent of TREM2, M -MA blocks Src-STAT1mediated inflammatory polarization and reduces the production of immune suppressors TAX1BP1 and PLAC8. Whole genome methylation analyses revealed M-MA's ability to erase the methylation memory of exhausted monocytes, particularly restoring Plac8 methylation. Together, our data suggest M -MA as an effective agent in restoring monocyte homeostasis with a therapeutic potential for treating sepsis.