Adjunct Therapy With All-trans-Retinoic Acid Improves Therapeutic Efficacy Through Immunomodulation While Treating Tuberculosis With Antibiotics in Mice

Abstract

Tuberculosis is the second leading infectious killer after coronavirus disease 2019 (COVID-19). Standard antitubercular drugs exhibit various limitations like toxicity, long treatment regimens, and lack of effect against dormant and drug-resistant organisms. Here, we report that all-trans-retinoic acid (ATRA) improves Mycobacterium tuberculosis clearance in mice during treatment with the antitubercular drug isoniazid. Interestingly, ATRA promoted activities of lysosomes and mitochondria, and production of various inflammatory mediators in macrophages. Furthermore, ATRA upregulated the expression of genes of lipid metabolism pathways in macrophages. We demonstrated that ATRA activated the MEK/ERK pathway in macrophages in vitro and MEK/ERK and p38 MAPK pathways in mice. Finally, ATRA induced both Th1 and Th17 responses in lungs and spleens of M. tuberculosis-infected mice. Together, these data indicate that ATRA provides beneficial adjunct therapeutic value by modulating MEK/ERK and p38 MAPK pathways and thus warrants further testing for human use.