TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the pro-inflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates are important drivers of IL-1β-mediated proinflammatory eicosanoid signaling in humans with pulmonary TB disease. Host-directed therapies that mitigate such metabolic reprograming have potential to limit pulmonary inflammation and tissue damage. Graphical Abstract One Sentence Summary Remodeling of the tricarboxylic acid cycle, characterized by increases in the proinflammatory metabolite succinate and decreased itaconate, mediates proinflammatory eicosanoids signaling in humans with pulmonary tuberculosis through induction of IL-1β.