Effect of Apoptotic Cell Recognition on Macrophage Polarization and Mycobacterial Persistence

Fulco, Tatiana de Oliveira; Andrade, Priscila Ribeiro; Barbosa, Mayara Garcia de Mattos; Pinto, Thiago Gomes Toledo; Ferreira, Paula Fernandez; Ferreira, Helen; Nery, José Augusto da Costa; Real, Suzana Corte; Borges, Valéria M.; Moraes, Milton Ozório; Sarno, Euzenir Nunes; Sampaio, Elizabeth P.; Pinheiro, Roberta Olmo

doi:10.1128/iai.02194-14

Cited by 44 publications

(44 citation statements)

References 52 publications

(56 reference statements)

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“…A histological hallmark of L-lep skin lesions is the presence of foamy MΦs containing high amounts of bacilli [2–4]. As shown above, L-lep MΦs displayed less autophagy activation than T-lep MΦs (Fig 2A).…”

Section: Resultsmentioning

confidence: 90%

“…In contrast, apoptosis contributes to the persistence of infection. In this connection, our previous work demonstrated that even though the MΦ1 phenotype was predominant in T-lep lesions, efferocytosis contributed to the maintenance of a minimum of MΦ2 cells, which are essential for sustaining the infection in leprosy skin lesions [4]. …”

Section: Discussionmentioning

confidence: 99%

“…At the opposite end of the spectrum, lepromatous leprosy (L-lep) patients have a disseminated form, with several skin lesions, absence of granuloma formation, high amounts of type 2 foamy MΦs loaded with bacilli, and anti- M . leprae antibodies [2–4]. The existence of both poles is a direct reflection of the cytokine patterns found in their respective skin lesions.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

et al. 2017

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Leprosy is a chronic infectious disease that may present different clinical forms according to the immune response of the host. Levels of IFN-γ are significantly raised in paucibacillary tuberculoid (T-lep) when compared with multibacillary lepromatous (L-lep) patients. IFN-γ primes macrophages for inflammatory activation and induces the autophagy antimicrobial mechanism. The involvement of autophagy in the immune response against Mycobacterium leprae remains unexplored. Here, we demonstrated by different autophagic assays that LC3-positive autophagosomes were predominantly observed in T-lep when compared with L-lep lesions and skin-derived macrophages. Accumulation of the autophagic receptors SQSTM1/p62 and NBR1, expression of lysosomal antimicrobial peptides and colocalization analysis of autolysosomes revealed an impairment of the autophagic flux in L-lep cells, which was restored by IFN-γ or rapamycin treatment. Autophagy PCR array gene-expression analysis revealed a significantly upregulation of autophagy genes (BECN1, GPSM3, ATG14, APOL1, and TPR) in T-lep cells. Furthermore, an upregulation of autophagy genes (TPR, GFI1B and GNAI3) as well as LC3 levels was observed in cells of L-lep patients that developed type 1 reaction (T1R) episodes, an acute inflammatory condition associated with increased IFN-γ levels. Finally, we observed increased BCL2 expression in L-lep cells that could be responsible for the blockage of BECN1-mediated autophagy. In addition, in vitro studies demonstrated that dead, but not live M. leprae can induce autophagy in primary and lineage human monocytes, and that live mycobacteria can reduce the autophagy activation triggered by dead mycobacteria, suggesting that M. leprae may hamper the autophagic machinery as an immune escape mechanism. Together, these results indicate that autophagy is an important innate mechanism associated with the M. leprae control in skin macrophages.

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Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

et al. 2017

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“…In addition, this cytokine may be directly involved in the differentiation of M2 macrophages and in the maturation of phagolysosomes 40 41…”

Section: Discussionmentioning

confidence: 99%

“…During the process of cell death, this cytokine induces signalling pathways that lead to the activation of kinases, cleavage of caspase 3 and signal amplification for programmed cell death 38. Furthermore, the presence of TGF-β in the medium may also be associated with tissue repair in which the cytokine acts in conjunction with fibroblast growth factor (FGF)-band arginase 1 to induce the healing response, cell migration, division, proliferation, differentiation and angiogenesis 1 40…”

Section: Discussionmentioning

confidence: 99%