Matrix Metalloproteinase 9 Production by Monocytes is Enhanced by TNF and Participates in the Pathology of Human Cutaneous Leishmaniasis

Abstract

IntroductionCutaneous leishmaniasis (CL) due to L.braziliensis infection is characterized by a strong inflammatory response with high levels of TNF and ulcer development. Less attention has been given to the role of mononuclear phagocytes to this process. Monocytes constitute a heterogeneous population subdivided into classical, intermediate and non-classical, and are known to migrate to inflammatory sites and secrete inflammatory mediators. TNF participates in the induction of matrix metalloproteinases (MMPs). MMP-9 is an enzyme that degrades basal membrane and its activity is controlled by the tissue inhibitor of metalloproteinase.MethodsMononuclear cells were obtained from ex-vivo labeling sub-populations of monocytes and MMP-9, and the frequency was determined by flow cytometry. Culture was performed during 72 hours, stimulating the cells with SLA, levels of MMP-9 and TIMP-1 in the supernatants were determined by ELISA.ResultsWe observed that cells from CL lesions secrete high amounts of MMP-9 when compared to healthy subjects. Although MMP-9 was produced by monocytes, non-classical ones were the main source of this enzyme. We also observed that TNF produced in high level during CL contributes to MMP-9 production.ConclusionsThese observations emphasize the role of monocytes, TNF and MMP-9 in the pathogenesis of L. braziliensis infection.

Characterization of the Histopathologic Features in Patients in the Early and Late Phases of Cutaneous Leishmaniasis

“…These molecules contribute to necrosis and cell recruitment to the site of infection. Monocytes and macrophages are heterogeneous subpopulations, with killing, inflammatory, and regulatory profiles 34. Previous studies have shown a high frequency of monocytes with inflammatory profile in E-CL,14 and there is a direct correlation between the frequency of monocytes expressing toll-like receptor9 with ulcer size in CL 37.…”

Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection

“…Such exaggerated expression of MMP1 has been observed to contribute to tissue destruction and disease progression in a number of other clinical contexts, including progression of rheumatoid arthritis (Xu et al, 2015), chronic obstructive pulmonary disease, acute respiratory distress syndrome, sarcoidosis, and tuberculosis (Elkington and Friedland, 2006). The pro-inflammatory cytokine tumor necrosis factor (TNF), which characterizes human CL caused by L. braziliensis (Castes et al, 1993; Ribeiro-de-Jesus et al, 1998), could be contributing to exaggerated expression of matrix metalloproteinases (Campos et al, 2014; Lehmann et al, 2005). TNF is known to accelerate degradation of type I collagens by MMP-1 leading to their gradual loss in human skin (Agren et al, 2015).…”

“…As we observed in CL lesions, there was an exaggerated expression of MMP1 following infection of macrophages in vitro . High levels of TNF are produced following infection of monocytes with L. braziliensis (Campos et al, 2014). Thus it seems likely that high levels of MMP1 associated with CL pathogenesis may be contributed to by a direct effect of the parasite on macrophage function.…”

A Potential Role for Mononuclear Phagocytes in Cutaneous Ulcer Development in Human Immunodeficiency Virus–Leishmania braziliensis Coinfection

“…12 Products secreted by monocytes during CL include TNF, chemokines (CXCL9, CXCL10, and CCL2), and metalloproteinase-9 (MMP-9), and some reports indicate the participation of TNF and monocyte-derived MMP-9 in tissue damage during leishmaniasis. 2,13,14 Herein, we evaluated the immune response from a patient with HIV and L. braziliensis coinfection and found mononuclear phagocytes infiltrating the lesion and production of TNF, CCL2, and MMP-9 at lesion site.…”