PGL I expression in live bacteria allows activation of a CD206/PPARγ cross-talk that may contribute to successful Mycobacterium leprae colonization of peripheral nerves

Abstract

Mycobacterium leprae, an obligate intracellular bacillus, infects Schwann cells (SCs), leading to peripheral nerve damage, the most severe leprosy symptom. In the present study, we revisited the involvement of phenolic glycolipid I (PGL I), an abundant, private, surface M. leprae molecule, in M. leprae-SC interaction by using a recombinant strain of M. bovis BCG engineered to express this glycolipid. We demonstrate that PGL I is essential for bacterial adhesion and SC internalization. We also show that live mycobacterium-producing PGL I induces the expression of the endocytic mannose receptor (MR/CD206) in infected cells in a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent manner. Of note, blocking mannose recognition decreased bacterial entry and survival, pointing to a role for this alternative recognition pathway in bacterial pathogenesis in the nerve. Moreover, an active crosstalk between CD206 and the nuclear receptor PPARγ was detected that led to the induction of lipid droplets (LDs) formation and prostaglandin E2 (PGE2), previously described as fundamental players in bacterial pathogenesis. Finally, this pathway was shown to induce IL-8 secretion. Altogether, our study provides evidence that the entry of live M. leprae through PGL I recognition modulates the SC phenotype, favoring intracellular bacterial persistence with the concomitant secretion of inflammatory mediators that may ultimately be involved in neuroinflammation.

Upregulation of Cytokines and Differentiation of Th17 and Treg by Dendritic Cells: Central Role of Prostaglandin E2 Induced by Mycobacterium bovis

“…PGE2 is synthesized from COX-2-derived PGH2 and functions through four G-protein-coupled E-type prostanoid (EP) receptors, namely, EP1, EP2, EP3, and EP4, each of which can activate different downstream signaling pathways [30]. In addition, it was demonstrated that PGE2 makes a contribution to mycobacterial infection by Mycobacterium leprae [31] and M. tb [14,32]. Similar results were obtained in this study.…”

Mycobacterium leprae promotes triacylglycerol de novo synthesis through induction of GPAT3 expression in human premonocytic THP-1 cells

“…Recently, we have reported that activation of PPARγ and PPARδ is important for lipid accumulation in M. leprae-infected THP-1 cells [40]. In Schwann cells, phenolic glicolipid-1 (PGL-1) of M. leprae promoted lipid droplet formation by activating crosstalk between CD206 and PPARγ [41]. Therefore, M. leprae might utilize the signal transduction pathway(s) mediated by PPARγ to induce GPAT3 expression in infected cells.…”

Macrophage Polarization in Leprosy–HIV Co-infected Patients

“…Previous studies have demonstrated that HIV-1 infection of macrophages prime or induce their polarization toward a proinflammatory phenotype that contributes to the establishment and maintenance of a state of chronic activation that is credited to represent a major determinant of HIV disease progression (36)(37)(38). In the present study, we selected a group of genes previously described as involved in leprosy pathogenesis (3,5,6,(39)(40)(41)(42)(43)(44)(45). Analysis of cell phenotype revealed an increase of anti-inflammatory cell markers in RR/HIV when compared with RR cells.…”