Modulation of lipid droplets by Mycobacterium leprae in Schwann cells: a putative mechanism for host lipid acquisition and bacterial survival in phagosomes

Mattos, Katherine Antunes de; Lara, Flávio Alves; Oliveira, Viviane G. C.; Rodrigues, Luciana Silva; D’Avila, Heloísa; Melo, Rossana C. N.; Manso, Pedro Paulo de Abreu; Sarno, Euzenir Nunes; Bozza, Patrı́cia T.; Pessolani, Maria Cristina Vidal

doi:10.1111/j.1462-5822.2010.01533.x

Cited by 134 publications

(199 citation statements)

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Section: Discussionmentioning

confidence: 99%

“…Of note, high amounts of iron were only found in LL macrophages and none was detected in epithelioid macrophages whereas small foci of iron deposits in vaguely differentiated macrophages were seen in BT lesions. With reference to a previous description of the accumulation of lipid droplets in LL lesions [36], we could infer that ML associates with lipid vesicles as a mechanism for transferring iron from the host to ML-rich phagosomes.As a whole, our results seem to clearly suggest that, on the one hand, CD163 may contribute to polarize LL macrophages to an anti-inflammatory phenotype by increasing the expression and levels of the immunoregulatory molecules IL-10 and IDO, although the other primary determinants of polarity in leprosy immune responses need to be better understood. In addition CD163 also contributes to ML uptake and increased amounts of iron, thus favoring bacterial survival and persistence.…”

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CD163 favors Mycobacterium leprae survival and persistence by promoting anti‐inflammatory pathways in lepromatous macrophages

et al. 2012

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Lepromatous macrophages possess a regulatory phenotype that contributes to the immunosuppression observed in leprosy. CD163, a scavenger receptor that recognizes hemoglobin-haptoglobin complexes, is expressed at higher levels in lepromatous cells, although its functional role in leprosy is not yet established. We herein demonstrate that human lepromatous lesions are microenvironments rich in IDO + CD163 + . Cells isolated from these lesions were CD68 + IDO + CD163 + while higher levels of sCD163 in lepromatous sera positively correlated with IL-10 levels and IDO activity. Different Mycobacterium leprae (ML) concentrations in healthy monocytes likewise revealed a positive correlation between increased concentrations of the mycobacteria and IDO, CD209, and CD163 expression. The regulatory phenotype in ML-stimulated monocytes was accompanied by increased TNF, IL-10, and TGF-β levels whereas IL-10 blockade reduced ML-induced CD163 expression. The CD163 blockade reduced ML uptake in human monocytes. ML uptake was higher in HEK293 cells transfected with the cDNA for CD163 than in untransfected cells. Simultaneously, increased CD163 expression in lepromatous cells seemed to be dependent on ML uptake, and contributed to augmented iron storage in lepromatous macrophages. Altogether, these results suggest that ML-induced CD163 expression modulates the host cell phenotype to create a favorable environment for mycobacterial entry and survival.Keywords: CD163 r IL-10 r Leprosy r Macrophages IntroductionLeprosy is an infectious disease caused by Mycobacterium leprae (ML) in which susceptibility to the mycobacteria and its clinicalmanifestations are attributed to the host immune response. The clinical and immunological patterns of this unique chronic infectious disease clearly demonstrate a continuous scale of changes in histological lesions. Disease classification is defined Correspondence: Dr. Euzenir N. Sarno e-mail: euzenir@fiocruz.br within two poles (tuberculoid to lepromatous) with transitions between these clinical forms. While typical epithelioid macrophages predominate at the paucibacillary tuberculoid pole of the disease, inactivated foamy macrophages predominate at the lepromatous end [1]. In lepromatous leprosy (LL), the lack of systemic inflammatory signals and corresponding local ones strongly indicates that a complex anti-inflammatory network is at work. In this * These authors contributed equally to this work as first authors. * * These authors contributed equally to this work as senior authors. Eur. J. Immunol. 2012. 42: 2925-2936 regard, neuroendocrine system involvement, in conjunction with the existence of multiple suppressive pathways under the control of the innate and adaptive immune response, has been reported [2][3][4][5][6][7].We have suggested that IDO may play a role in a hitherto unknown suppressive mechanism in leprosy [6]. It has also been reported that accumulated oxidized host phospholipids in lepromatous macrophages downregulate the innate immune response [8]. Foamy macrophages seem to sust...

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Section: Discussionmentioning

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CD163 favors Mycobacterium leprae survival and persistence by promoting anti‐inflammatory pathways in lepromatous macrophages

et al. 2012

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“…This activity can have a profound impact on monocyte immune functions, since a relationship between perilipin expression and innate immunity reactions has been recently demonstrated. For example, PLIN2 expression is increased during innate immunity response against leprosy (Mattos et al, 2011), and regulates MCP1 production by human monocytes (Wurfel et al, 2005). PLIN2 was also found to be involved in dendritic cell antigen presentation (Bougnères et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Effects of EPA and DHA on lipid droplet accumulation and mRNA abundance of PAT proteins in caprine monocytes

Lecchi

Invernizzi

Agazzi

et al. 2013

Research in Veterinary Science

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a b s t r a c tThe present study investigated the in vitro effects on caprine monocytes of two x-3 PUFAs, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on lipid droplet formation, an emerging process of fundamental importance in innate immunity regulation. The mRNA abundance of PAT protein family (PLIN1, PLIN2 and PLIN3), involved in the formation and trafficking of the droplets, was also assessed. The effects of EPA and DHA on monocyte apoptosis were studied as well. The number of lipid droplets per cell was found to be dependent on both type and concentration of fatty acid. x-3 PUFAs upregulated PLIN3 and PLIN2 gene expression, as well as apoptosis rate. The present findings suggest that PUFA might modify innate immune functions of goat monocytes by interfering with the formation of lipid droplets and by upregulating proteins belonging to PAT protein family.

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“…We showed recently that M. leprae induces LD biogenesis and accumulation in bacterial-containing phagosomes in SCs and is responsible, at least in part, for originating foamy degeneration of M. lepraeinfected SCs in LL nerves (22). Accordingly, as was proposed for macrophages in the context of dermal lesions (9,23), it is reasonable to speculate that the lipid-storage phenomenon observed in M. leprae-infected SCs is an important contributor to the immunoinflammatory function of these cells in LL nerve lesions.…”

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

Mattos

Oliveira

D’Avila

et al. 2011

The Journal of Immunology

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The mechanisms responsible for nerve injury in leprosy need further elucidation. We recently demonstrated that the foamy phenotype of Mycobacterium leprae-infected Schwann cells (SCs) observed in nerves of multibacillary patients results from the capacity of M. leprae to induce and recruit lipid droplets (LDs; also known as lipid bodies) to bacterial-containing phagosomes. In this study, we analyzed the parameters that govern LD biogenesis by M. leprae in SCs and how this contributes to the innate immune response elicited by M. leprae. Our observations indicated that LD formation requires the uptake of live bacteria and depends on host cell cytoskeleton rearrangement and vesicular trafficking. TLR6 deletion, but not TLR2, completely abolished the induction of LDs by M. leprae, as well as inhibited the bacterial uptake in SCs. M. leprae-induced LD biogenesis correlated with increased PGE2 and IL-10 secretion, as well as reduced IL-12 and NO production in M. leprae-infected SCs. Analysis of nerves from lepromatous leprosy patients showed colocalization of M. leprae, LDs, and cyclooxygenase-2 in SCs, indicating that LDs are sites for PGE2 synthesis in vivo. LD biogenesis Inhibition by the fatty acid synthase inhibitor C-75 abolished the effect of M. leprae on SC production of immunoinflammatory mediators and enhanced the mycobacterial-killing ability of SCs. Altogether, our data indicated a critical role for TLR6-dependent signaling in M. leprae–SC interactions, favoring phagocytosis and subsequent signaling for induction of LD biogenesis in infected cells. Moreover, our observations reinforced the role of LDs favoring mycobacterial survival and persistence in the nerve. These findings give further support to a critical role for LDs in M. leprae pathogenesis in the nerve.

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Modulation of lipid droplets by Mycobacterium leprae in Schwann cells: a putative mechanism for host lipid acquisition and bacterial survival in phagosomes

Cited by 134 publications

References 55 publications

CD163 favors Mycobacterium leprae survival and persistence by promoting anti‐inflammatory pathways in lepromatous macrophages

CD163 favors Mycobacterium leprae survival and persistence by promoting anti‐inflammatory pathways in lepromatous macrophages

Effects of EPA and DHA on lipid droplet accumulation and mRNA abundance of PAT proteins in caprine monocytes

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

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