The function of peroxisome proliferator-activated receptors PPAR-γ and PPAR-δ in Mycobacterium leprae-induced foam cell formation in host macrophages

Abstract

Leprosy is a chronic infectious disease caused by Mycobacterium leprae ( M . leprae ). In lepromatous leprosy (LL), skin macrophages, harboring extensive bacterial multiplication, gain a distinctive foamy appearance due to increased intracellular lipid load. To determine the mechanism by which M . leprae modifies the lipid homeostasis in host cells, an in vitro M . leprae infection system, using human macrophage precursor THP-1 cells and M . leprae prepared from the footpads of nude mice, was employed. RNA extracted from skin smear samples of patients was used to investigate host gene expressions before and after multidrug therapy (MDT). We found that a cluster of peroxisome proliferator-activated receptor (PPAR) target genes associated with adipocyte differentiation were strongly induced in M . leprae- infected THP-1 cells, with increased intracellular lipid accumulation. PPAR-δ and PPAR-γ expressions were induced by M . leprae infection in a bacterial load-dependent manner, and their proteins underwent nuclear translocalization after infection, indicating activation of PPAR signaling in host cells. Either PPAR-δ or PPAR-γ antagonist abolished the effect of M . leprae to modify host gene expressions and inhibited intracellular lipid accumulation in host cells. M . leprae -specific gene expressions were detected in the skin smear samples both before and after MDT, whereas PPAR target gene expressions were dramatically diminished after MDT. These results suggest that M . leprae infection activates host PPAR signaling to induce an array of adipocyte differentiation-associated genes, leading to accumulation of intracellular lipids to accommodate M . leprae parasitization. Certain PPAR target genes in skin lesions may serve as biomarkers for monitoring treatment efficacy.

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

“…In addition to GPAT3, PPARγ also targets ADRP [39], which has a similar induction following M. leprae infection in THP-1 cells [6]. 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].…”

“…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 .…”

Host-Related Laboratory Parameters for Leprosy Reactions

“…In addition to host-derived biomarkers, a few studies have investigated the components or derivatives of M. leprae for leprosy diagnosis and monitoring of treatment efficacy (136)(137)(138)(139). Specifically, M. leprae antigenic determinants have been demonstrated in dermal macrophages and SCs during T1R (38).…”

Essential Roles of PPARs in Lipid Metabolism during Mycobacterial Infection

“…The observed effects are blocked by PPAR-α antagonists and absent in PPAR-α-deficient mice. Recently, we found that PPAR-γ and PPAR-δ are activated in M. leprae -infected macrophages [ 22 ]. Infection with a recombinant strain of M. bovis BCG that produces phenolic glycolipid-1 (PGL-1) of M. leprae activates PPAR-γ in primary cultures of human Schwann cells [ 23 ].…”

“…Recently, in M. leprae -infected THP-1 cells, we reported that the increased expression of PPAR-γ and PPAR-δ coincided with the induction of intracellular lipid droplet formation [ 22 ]. Further, the expression of the PPAR-γ target genes ADRP , scavenger receptor CD36 , fatty acid-binding protein 4 ( FABP4 ), and apolipoprotein C-1 ( APOC1 ) were significantly increased.…”