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

TLDR

Leprosy is characterized by foamy macrophages that accumulate lipid droplets, but the origin, nature, and role of these organelles in disease remain unclear. The study aims to demonstrate that foamy macrophages in leprosy lesions arise from lipid droplet accumulation induced by Mycobacterium leprae infection. The authors used in vivo mouse pleurisy and in vitro monocyte/macrophage cultures to show that Mycobacterium leprae induces lipid droplet formation, which is propagated to neighboring cells through a TLR2/6‑dependent paracrine signal. The study found that Mycobacterium leprae–induced lipid droplets are propagated via a TLR2/6‑dependent paracrine signal, that other innate receptors also contribute to droplet formation, and that droplet accumulation correlates with PGE2 production, positioning these organelles as key sites for eicosanoid synthesis and immune modulation in leprosy.

Abstract

Abstract Lipid droplets induced by Mycobacterium leprae in macrophages are Toll-like receptor-regulated organelles involved in eicosanoid formation and leprosy pathogenesis. 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 PGE2 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.