A mycobacterial ligand coordinates multi-receptor signaling to reprogram macrophage lipid metabolism

Abstract How innate immune receptors integrate signals from complex microbial ligands remains poorly understood. Here, we show that a single microbial component can encode coordinated engagement of two pattern-recognition receptors to reprogram macrophage lipid metabolism and drive foam cell formation, a hallmark of necrotizing tuberculosis lesions. These lipid-laden macrophages are defined by the accumulation of cytosolic lipid droplets enriched in neutral lipids. The mycobacterial lipoglycan mannose-capped lipoarabinomannan (ManLAM) drives macrophage lipid droplet accumulation through combined activation of Toll-like receptor 2 (TLR2) and Dectin-2, with distinct structural moieties selectively mediating recognition by each receptor. Dual receptor engagement induces lipid metabolic reprogramming and enhances NF-kB-mediated inflammatory signaling, with lipid accumulation proceeding through an mTORC1-PPARγ-dependent pathway that is largely independent of NF-kB activation. ManLAM-induced lipid metabolic changes closely mirror those elicited during Mycobacterium tuberculosis infection, both in neutral lipid composition and in dependence on the mTORC1-PPARγ axis. These findings identify ManLAM as a major mycobacterial driver of foam cell-associated lipid metabolism and suggest that the architecture of complex microbial ligands can organize multi-receptor signaling.