Nur77 influences immunometabolism to regulate the release of proinflammatory cytokines and the formation of lipid bodies during Mycobacterium tuberculosis infection of macrophages.

Abstract

Infection of macrophages with Mycobacterium tuberculosis induces innate immune responses designed to clear the invading bacterium. However, bacteria often survive within the intracellular environment by exploiting these responses triggered by macrophages. Here, the role of the orphan nuclear receptor Nur77 (Nr4a1), in regulating the response of macrophages infected with M. tuberculosis, has been delineated. Nur77 is induced early during infection, regulates metabolism by binding directly at the promoter of the TCA cycle enzyme, isocitrate dehydrogenase 2 (IDH2) to act as its repressor, and shifts the balance from a proinflammatory to an anti-inflammatory phenotype Depletion of Nur77 increased transcription of IDH2 and consequently, the levels of intracellular succinate leading to enhanced levels of the proinflammatory cytokine, IL-1β. Further, Nur77 inhibited production of antibacterial nitric oxide and IL-1β in a succinate dehydrogenase (SDH)- dependent manner, suggesting that its induction favors bacterial survival by suppressing bactericidal responses. Indeed, depletion of Nur77 inhibited intracellular survival of M. tuberculosis. On the other hand, depletion of Nur77 enhanced lipid body formation suggesting that the fall in Nur77 levels as infection progresses, likely favors foamy macrophage formation and long-term survival of M. tuberculosis in the host milieu.