Lipid droplet formation in leprosy: Toll-like receptor-regulated organelles involved in eicosanoid formation and Mycobacterium leprae pathogenesis

Abstract

A hallmark of LL is the accumulation of Virchow's foamy macrophages. However, the origin and nature of these lipids, as well as their function and contribution to leprosy disease, remain unclear. We herein show that macrophages present in LL dermal lesions are highly positive for ADRP, suggesting that their foamy aspect is at least in part derived from LD (also known as lipid bodies) accumulation induced during ML infection. Indeed, the capacity of ML to induce LD formation was confirmed in vivo via an experimental model of mouse pleurisy and in in vitro studies with human peripheral monocytes and murine peritoneal macrophages. Furthermore, infected cells were shown to propagate LD induction to uninfected, neighboring cells by generating a paracrine signal, for which TLR2 and TLR6 were demonstrated to be essential. However, TLR2 and TLR6 deletions affected LD formation in bacterium-bearing cells only partially, suggesting the involvement of alternative receptors of the innate immune response besides TLR2/6 for ML recognition by macrophages. Finally, a direct correlation between LD formation and PGE(2) production was observed, indicating that ML-induced LDs constitute intracellular sites for eicosanoid synthesis and that foamy cells may be critical regulators in subverting the immune response in leprosy.

Butyrate-Mediated Genomic Changes Involved in Non-Specific Host Defenses, Matrix Remodeling and the Immune Response in the Rumen Epithelium of Cows Afflicted With Subacute Ruminal Acidosis

“…In addition, Li et al (2011) were able to determine that NEDD4L is a positive regulator of NF-κB which is in agreement with our results. Similarly, the ability of MAP3K8 and PLIN2 to activate the NF-κB pathway has been documented (Chan and Reed, 2005;Cismasiu et al, 2009;Mattos et al, 2010). These direct relationships are supported by results presented here.…”

Diverse Bacteria Promote Macrophage Foam Cell Formation Via Toll-Like Receptor-Dependent Lipid Body Biosynthesis

“…2, 3). Earlier reports that C. pneumoniae-or mycobacteria-induced foam cell formation was reduced in TLR2-deficient macrophages [31][32][33] , and the observation that LPS promotes macrophage lipid accumulation 34) , also support this conclusion. To date, the most widely studied potential mechanism for the generation of foam cells in atheroma has been the uptake of oxidised LDL by macrophage scavenger receptors 2) ; however, the results of this and pre-the absence of overt infections.…”

TLR6-Driven Lipid Droplets in Mycobacterium leprae-Infected Schwann Cells: Immunoinflammatory Platforms Associated with Bacterial Persistence

“…Our previous data also indicated that Mycobacterium-induced LD formation in infected macrophages depends on bacterial recognition via TLRs. Accordingly, we showed recently that TLR2 and TLR6 pathways are preferentially activated during LD biogenesis triggered by M. bovis BCG and M. leprae infection in macrophages (9,11,12,15).…”

“…These lipids were initially thought to be derived from M. leprae, such as phthiocerol dimycocerosate/ dimycocerosate and phenolic glycolipid-1 (PGL-1) (6, 7). However, very recently, a more detailed analysis of the lipid metabolism in LL lesions indicated that the foamy aspect is due mostly to the accumulation of host-derived lipids, such as oxidized phospholipids and cholesterol ester (8,9).These lipids were shown to be stored in nonmembrane-bound cytoplasmic organelles known as lipid bodies or lipid droplets (LDs) (9).…”

“…Contemporary evidence points to LDs as inflammatory organelles involved in the synthesis and secretion of inflammatory mediators (10). Our group recently demonstrated that the LDs formed in response to bacillus Calmette-Guérin (BCG) and M. leprae constitute sites for eicosanoid synthesis, ultimately leading to increased production of PGE 2 by infected macrophages (9,11,12). PGE 2 is a potent immune modulator that downregulates Th1 responses and bactericidal activity toward intracellular organisms (12)(13)(14).…”