Immunoregulatory macrophages induced by mycobacterial nonpolar lipids

Abstract The capacity of Mycobacterium tuberculosis (Mtb) to establish long-term survival is attributed to its ability to subvert host defense mechanisms, especially macrophages. Although Mtb lipids are believed to play a role in this host-pathogen crosstalk, how mycobacterial lipids drive this complex interaction is poorly characterized. Here, we cultured macrophages with nonpolar cell wall Mtb lipids and applied high-throughput expression profiling (RNA sequencing), mass spectrometry–based targeted eicosanoid, and untargeted lipidomics analysis. This system-level analysis revealed that Mtb nonpolar lipid triggered the expression of phenotypic markers for classically and alternatively activated macrophages, a state previously referred as immunoregulatory. Specifically, under lipid stimulation, macrophages expressed high levels of proinflammatory markers, activated components of the interleukin-1 family, underwent an imbalance in lipid metabolism, and shifted the eicosanoid synthesis pathway toward the prostaglandin axis. Taken together, these results suggest an intricate mechanism of Mtb-driven macrophage immunomodulation that may favor its long-term survival.