Long?term culture of multibacillary leprosy macrophages isolated from skin lesions: a new model to study Mycobacterium leprae?human cell interaction

Moura, Danielle F.; Teles, Rosane M. B.; Ribeiro-Carvalho, Marilza Moura; Santos, I M C F; Ferreira, Helen; Fulco, T O; Nery, José A. C.; Sampaio, Elizabeth P.; Sarno, Euzenir Nunes

doi:10.1111/j.1365-2133.2007.07992.x

Cited by 17 publications

(13 citation statements)

References 26 publications

(42 reference statements)

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“…To confirm that MΦs are able to activate autophagy in response to mycobacteria in leprosy lesions, M . leprae -infected dermal MΦs were obtained directly from fresh skin lesion biopsies, as previously described [41]. The phenotype of the isolated cells from T-lep and L-lep skin lesions was determined by immunofluorescence staining of the human MΦ marker CD68.…”

Section: Resultsmentioning

confidence: 99%

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: 99%

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

et al. 2017

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“…TH2 cytokines like IL-4 and IL-10 were previously shown to predominate in lepromatous leprosy lesions (19,22) and to downregulate MMP-9 (4). However, the effects of TH1 cytokines are not as clear.…”

Section: Discussionmentioning

confidence: 99%

High Matrix Metalloproteinase Production Correlates with Immune Activation and Leukocyte Migration in Leprosy Reactional Lesions

Teles

Amadeu

et al. 2010

Infect Immun

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Matrix metalloproteinases (MMPs) compose a family of zinc-and calcium-dependent proteolytic enzymes responsible for extracellular matrix (ECM) remodeling and the regulation of the trans-ECM migration of leukocytes, an important step in inflammatory processes as well as infectious diseases. MMPs are functionally classified according to their relative substrate specificities but have been shown to overlap. Collagenases (MMP-1, -8, and -13) degrade type I collagen, whereas gelatinases A and B (MMP-2 and -9, respectively) degrade denatured type I (gelatin) and type IV collagens, a major component of the basement membrane. Collagenases are produced by many cell types including lymphocytes, granulocytes, astrocytes, and activated macrophages (10, 18).MMP secretion takes place under tight regulatory mechanisms including transcriptional controls in addition to their release as proenzymes, requiring activation by specific proteases and cytokines present in the milieu (2,3,16). Also, the postactivation of MMPs is controlled by metalloproteinase tissue inhibitors (tissue inhibitor of MMP [TIMP]), a family of specific inhibitors, that bind to MMPs in a stoichiometric ratio.

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“…There is a possibility that this same mechanism occurs in leprosy infection. Our previous data indicated that NO predominates in BT lesions and that macrophages isolated from LL lesions acquire the capacity to produce NO [8]. While responsible for inducing tissue damage and inflammation, iNOS and other reactive oxygen species (ROS) from the respiratory burst are hypothesized to be the most efficient bactericidal mechanism against M. leprae.…”

Section: Hla-drmentioning

confidence: 99%

“…In a previous study, it was demonstrated that CD68-positive macrophages isolated from LL lesions suffered morphological and functional changes in culture, suggesting an environmental-dependent state [8], which the naturally occurring reversal reaction (RR) phenomenon seems to confirm [9,10].…”

Section: Introductionmentioning

confidence: 97%