Mycobacterium tuberculosisModulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival

Abstract

Mycobacterium tuberculosis–macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis–macrophage lipids can interact with host peroxisome proliferator-activated receptor γ and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor γ and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation.

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

“…PPAR␥ and TR4 provoke anti-inflammatory and pro-mycobacterium properties of macrophages (16,17,25), whereas vitamin D receptor and LXRs on the other hand have anti-inflammatory but anti-infective or bactericidal properties (39,40). Similarly, we observe that Rev-erb␣ facilitates M. tuberculosis clearance as an effect of its role in reducing IL10 production (Fig.…”

“…Rev-erb␣ Knockdown Cells Are More Susceptible to M. tuberculosis-Our previous study has illustrated the role of nuclear receptors in modulating macrophage effector functions in mycobacterial clearance and survival (16). Given that Reverb␣ finds enhanced expression in bactericidal M1 macrophages, we investigated its antimycobacterial role.…”

Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis

“…Blood was left to clot at room temperature for 10 min and then centrifuged at 1200 rpm for 10 min following which serum was collected and cytokines were assayed with ELISA kits. To determine arginase activity, production of urea from arginine was determined colorimetrically as described previously (32).…”

Mycobacterium tuberculosisKeto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair

“…Within the host macrophage, in addition to membrane receptors involved in the phagocytosis of the pathogen, TLRs and some nuclear receptors are considered to be important lipid sensors as well as integrators of lipid signaling, and they have been shown to be integral elements of foamy biogenesis (27)(28)(29)(30)(31). Testicular receptor 4 (TR4), peroxisome proliferator-activated receptor (PPAR), and liver X receptor (LXR) function as fatty acid sensors and can sense an array of complex lipids (28,(31)(32)(33).…”