Lipid droplet formation in leprosy: Toll-like receptor-regulated organelles involved in eicosanoid formation and Mycobacterium leprae 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 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.
Mattos
Katherine A
KA
Laboratórios de Microbiologia Celular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
D'Avila
Heloisa
H
Rodrigues
Luciana S
LS
Oliveira
Viviane G C
VG
Sarno
Euzenir N
EN
Atella
Georgia C
GC
Pereira
Geraldo M
GM
Bozza
Patricia T
PT
Pessolani
Maria Cristina V
MC
D000818:Animals; D001706:Biopsy; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D015777:Eicosanoids / Q000096:biosynthesis*; D006801:Humans; D007918:Leprosy / Q000378:metabolism* / Q000382:microbiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009166:Mycobacterium leprae / Q000187:drug effects / Q000472:pathogenicity*; D015388:Organelles / Q000378:metabolism* / Q000382:microbiology; D019899:Paracrine Communication / Q000187:drug effects; D000070780:Perilipin-2; D010587:Phagocytosis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000382:microbiology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
D017077:Culture Media, Conditioned; D015777:Eicosanoids; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; D015232:Dinoprostone