PPARγ Expression and Function in Mycobacterial Infection: Roles in Lipid Metabolism, Immunity, and Bacterial Killing

Abstract

Tuberculosis continues to be a global health threat, with drug resistance and HIV coinfection presenting challenges for its control. Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a highly adapted pathogen that has evolved different strategies to subvert the immune and metabolic responses of host cells. Although the significance of peroxisome proliferator-activated receptor gamma (PPARγ) activation by mycobacteria is not fully understood, recent findings are beginning to uncover a critical role for PPARγ during mycobacterial infection. Here, we will review the molecular mechanisms that regulate PPARγ expression and function during mycobacterial infection. Current evidence indicates that mycobacterial infection causes a time-dependent increase in PPARγ expression through mechanisms that involve pattern recognition receptor activation. Mycobacterial triggered increased PPARγ expression and activation lead to increased lipid droplet formation and downmodulation of macrophage response, suggesting that PPARγ expression might aid the mycobacteria in circumventing the host response acting as an escape mechanism. Indeed, inhibition of PPARγ enhances mycobacterial killing capacity of macrophages, suggesting a role of PPARγ in favoring the establishment of chronic infection. Collectively, PPARγ is emerging as a regulator of tuberculosis pathogenesis and an attractive target for the development of adjunctive tuberculosis therapies.

Figure 1

Model of PPARγ functions in mycobacterial infection. The activation of macrophage TLR2 signaling by M. tuberculosis, ManLAM, or M. bovis BCG results in the activation of PPARγ and NF-κB. The activation of PPARγ by mycobacterial infection induces lipid droplet formation, PGE₂ production and favors mycobacterial survival. Moreover, the PPARγ activation can down-modulate NF-κB activity inhibiting the proinflammatory cytokine production. Both inhibition of PPARγ with the selective antagonist GW9662 or PPARγ knockdown with siRNA result in a reduction of lipid droplet biogenesis and increased Mycobacterium killing by macrophages.