PPARγExpression 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.

Liposomal delivery of lipoarabinomannan triggers Mycobacterium tuberculosis specific T-cells

“…In searching for an alternative approach to quantify the biological activity of LIPLAM, we measured the protein expression of PPARg in CD1 þ APCs. PPARg belongs to the superfamily of lipid-activator nuclear receptors and the expression in macrophages is modulated by purified LAM [38]. Untreated CD1 þ APCs expressed basal protein levels of PPARg ( Figure 4A) as has been reported for IL-4/IL-13-mediated alternatively activated macrophages [39].…”

Modulation of host ubiquitin system genes in human endometrial cell line infected with Mycobacterium tuberculosis

“…Further, mkrn1 induces ubiquitination of pparγ, followed by its proteasome-dependent degradation [20]. High levels of pparγ have been shown to favor mycobacterial growth [21], and thus, high levels of mkrn1 as observed in our study could lead to degradation of pparγ as host survival mechanism.…”

Impacts of peroxisome proliferator-activated receptor-γ activation on cigarette smoke-induced exacerbated response to bacteria

“…This contrasts with the positive impact of PPARγ activation on efferocytosis capacity [26]. Moreover, it is unlikely that bacterial killing capacity of the macrophages is improved with PPARγ agonists, as studies showed that Mycobacterium tuberculosis uses PPARγ activation as a mechanism to survive within macrophages [31]. Also, improved bacterial clearance does not seem to be due to an increase in soluble anti-bacterial factors, such as defensins, as rosiglitazone did not affect the bactericidal activity of BALF.…”