High matrix metalloproteinase production correlates with immune activation and leukocyte migration in leprosy reactional lesions.
ABSTRACT Gelatinases A and B (matrix metalloproteinase 2 [MMP-2] and MMP-9, respectively) can induce basal membrane breakdown and leukocyte migration, but their role in leprosy skin inflammation remains unclear. In this study, we analyzed clinical specimens from leprosy patients taken from stable, untreated skin lesions and during reactional episodes (reversal reaction [RR] and erythema nodosum leprosum [ENL]). The participation of MMPs in disease was suggested by (i) increased MMP mRNA expression levels in skin biopsy specimens correlating with the expression of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), (ii) the detection of the MMP protein and enzymatic activity within the inflammatory infiltrate, (iii) increased MMP levels in patient sera, and (iv) the in vitro induction of MMP-9 by Mycobacterium leprae and/or TNF-alpha. It was observed that IFN-gamma, TNF-alpha, MMP-2, and MMP-9 mRNA levels were higher in tuberculoid than lepromatous lesions. In contrast, interleukin-10 and tissue inhibitor of MMP (TIMP-1) message were not differentially modulated. These data correlated with the detection of the MMP protein evidenced by immunohistochemistry and confocal microscopy. When RR and ENL lesions were analyzed, an increase in TNF-alpha, MMP-2, and MMP-9, but not TIMP-1, mRNA levels was observed together with stronger MMP activity (zymography/in situ zymography). Moreover, following in vitro stimulation of peripheral blood cells, M. leprae induced the expression of MMP-9 (mRNA and protein) in cultured cells. Overall, the present data demonstrate an enhanced MMP/TIMP-1 ratio in the inflammatory states of leprosy and point to potential mechanisms for tissue damage. These results pave the way toward the application of new therapeutic interventions for leprosy reactions.
Full-textDOI: · Available from: Rosane Teles, Jun 29, 2015
- SourceAvailable from: Tripti De[Show abstract] [Hide abstract]
ABSTRACT: Visceral leishmaniasis caused by the intracellular parasite Leishmania donovani is a major public health problem in the developing world. The emergence of increasing number of L. donovani strains resistance to antimonial drugs recommended worldwide requires the intervention of effective vaccine strategy for treatment of VL. In the present study L. donovani culture derived, soluble, secretory serine protease (pSP) has been shown to be vaccine target of VL. Protection from VL could be achieved by the use of safer vaccine which generally requires an adjuvant for induction of strong Th1 response. To assess the safety, immunogenicity and efficacy of pSP as vaccine candidate in mouse model we used IL-12 as adjuvant. BALB/c mice immunized with pSP+IL-12 were protected significantly from challenged infection even after four months by reducing the parasite load in liver and spleen and suppressed the development of the disease along with an increase in IgG2a antibody level in serum, enhanced delayed type hypersensitivity and strong T-cell proliferation. Groups receiving pSP+IL-12 had an augmented pSP antigen specific Th1 cytokines like IFN-γ and TNF-α response with concomitant decrease of Th2 cytokines IL-4 and IL-10 after vaccination. In this study the vaccine efficacy of pSP was further assessed for its prophylactic potential by enumerating matrix metalloprotease-9 (MMP-9) profile which has been implicated in various diseases. MMP-9 associated with different microbial infections is controlled by their natural inhibitors (TIMPS) and by some cytokines. In this study pSP was found to regulate excessive inflammation by modulating the balance between MMP-9 and TIMP-1 expression. This modulatory effect has also been demonstrated by IFN-γ mediated down regulation of TNF-α induced MMP-9 expression in activated murine macrophages. This is the first report where a secretory L. donovani serine protease (pSP) adjuvanted with IL-12 could also act as protective imunogen by modifying cytokine mediated MMP-9 expression in experimental VL. These findings elucidate the mechanisms of regulation of MMP-9 following infection of L. donovani in vaccinated animals and thus pave the way for developing new immunotherapeutic interventions for VL.Immunobiology 02/2012; 218(1). DOI:10.1016/j.imbio.2012.02.008 · 3.18 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Besides their evident importance in host defense, macrophages have been shown to play a detrimental role in different pathological conditions, including chronic inflammation, atherosclerosis, and cancer. Regardless of the exact situation, macrophage activation and migration are intimately connected to extracellular matrix degradation. This process is accomplished by multiple proteolytic enzymes, including serine proteases and members of the matrix metalloproteinase family. In this study, we have utilized qPCR arrays to simultaneously analyze the temporal expression pattern of a range of genes involved in extracellular matrix metabolism in the mouse derived-macrophage cell line RAW 264.7 following stimulation with LPS. Our results revealed that LPS induces the expression of matrix metalloproteinases while at the same time decreased the expression of matrix metalloproteinase inhibitors. The opposite scenario was found for the genes encoding serine proteases, which were downregulated while their inhibitors were upregulated. In addition, intergenic comparison of the expression levels of related proteases revealed large differences in their basal expression level. These data highlight the complexity of the gene expression regulation implicated in macrophage-dependent matrix degradation and furthermore emphasize the value of qPCR array techniques for the investigation of the complex regulation of the matrix degradome.Mediators of Inflammation 01/2012; 2012:157894. DOI:10.1155/2012/157894 · 2.42 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: After tuberculosis, leprosy (Mycobacterium leprae) and Buruli ulcer (M. ulcerans infection) are the second and third most common mycobacterial infections in humankind, respectively. Recent advances in both diseases are summarized. Leprosy remains a public health problem in some countries, and new case detections indicate active transmission. Newly identified M. lepromatosis, closely related to M. leprae, may cause disseminated leprosy in some regions. In genome-wide screening in China, leprosy susceptibility associates with polymorphisms in seven genes, many involved with innate immunity. World Health Organization multiple drug therapy administered for 1 or 2 years effectively arrests disseminated leprosy but disability remains a public health concern. Relapse is infrequent, often associated with higher pretreatment M. leprae burdens. M. ulcerans, a re-emerging environmental organism, arose from M. marinum and acquired a virulence plasmid coding for mycolactone, a necrotizing, immunosuppressive toxin. Geographically, there are multiple strains of M. ulcerans, with variable pathogenicity and immunogenicity. Molecular epidemiology is describing M. ulcerans evolution and genotypic variants. First-line therapy for Buruli ulcer is rifampin + streptomycin, sometimes with surgery, but improved regimens are needed. Leprosy and Buruli ulcer are important infections with significant public health implications. Modern research is providing new insights into molecular epidemiology and pathogenesis, boding well for improved control strategies.Current Opinion in Infectious Diseases 10/2010; 23(5):445-55. DOI:10.1097/QCO.0b013e32833c2209 · 5.03 Impact Factor