Mycobacterium tuberculosis 19-kDa lipoprotein induces Toll-like receptor 2-dependent peroxisome proliferator-activated receptor γ expression and promotes inflammatory responses in human macrophages

Abstract

Abstract. Mycobacterium tuberculosis (M.tb) enhances its survival in macrophages by suppressing immune responses, in part through its complex cell wall structures. M.tb 19-kDa lipoprotein (P19), a component of the complex cell wall structures of M.tb, is a Toll-like receptor (TLR) agonist, and may induce immune responses through TLR2. Furthermore, the activation of peroxisome proliferator-activated receptor γ (PPARγ) is also involved in M.tb-induced immune responses in macrophages. In the present study, specific agonists/antagonists and siRNA were used to investigate the role of PPARγ in P19-induced immune responses in human macrophages, including TLR2 activation, p38 phosphorylation and cytokine production. In the present study, PPARγ expression, p38 phosphorylation and cytokine production were upregulated following M.tb H37Rv infection or P19 treatment. By pretreating macrophages with a specific PPARγ agonist or antagonist, it was demonstrated that phosphorylation and IL-6 production are modulated in macrophages by PPARγ activity. Following TLR2 knockdown in macrophages, the expression of PPARγ was significantly decreased in the presence or absence of P19 treatment. Furthermore, p38 phosphorylation and cytokine production were significantly reduced in TLR2 knockdown macrophages following P19 treatment. It was demonstrated in the current study that PPARγ was induced and activated by M.tb infection and that P19-induced PPARγ expression, p38 phosphorylation and cytokine production in macrophages are dependent on TLR2. These findings suggest a role for PPARγ and TLR2 in P19-induced p38 phosphorylation and cytokine production, thereby potentially influencing M.tb pathogenesis.

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“…In addition to recognition of Mtb ligands and phagocytosis, macrophage receptors are also involved in the activation of specific downstream pathways. As an example, MR, a transmembrane C-type lectin, ligates Mtb lipoarabinomannan and activates macrophage peroxisome proliferator activated receptor gamma (PPAR γ ) expression in a phospholipase A2 and TLR-2 dependent manner [ 14 , 15 ]. In contrast to the avirulent vaccine strain Mycobacterium bovis Bacillus Calmette-Guérin (BCG), virulent Mtb activates macrophage PPAR γ and induces the production of cyclooxygenase 2 and IL-8, which regulate inflammatory responses via arachidonic acid metabolites and the recruitment of neutrophils, respectively [ 14 ].…”

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“…PPARγ is of particular interest as it is also highly expressed in alveolar macrophages, where it contributes to the formation of foam cells and promotes anti-inflammatory gene expression while transrepressing pro-inflammatory gene expression upon ligand binding 31 ; it also serves as a biological marker for alternatively activated macrophages (M2 phenotype) 32 . M. tuberculosis infection of macrophages induces PPARγ via the mannose receptor (MR, CD206) 33 and TLR2 34 and in turn increases M. tuberculosis intracellular growth, lipid body formation and chemokine release. PPARγ knock down followed by M. tuberculosis infection leads to decreased growth, and an increase in expression of 36 genes (including BAX) and a decrease in expression of 31 genes.…”

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“…These antigens induce apoptosis via the TLR2 pathway in macrophages. In addition, TLR2-mediated PPARγ expression is induced by 19-kDa lipoproteins, thereby promoting inflammatory responses by activating the MAPK pathway [91,92]. Additionally, 19-kDa lipoproteins are involved in IFN-γ signaling.…”