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 branchedmycolic acid derived from Mycobacterium bovis Bacillus Calmette–Gue´ rin (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-STAT1- mediated 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.