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

Abstract

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.

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

“…In addition to MMP-12, MMP-9 was also present in the top T-lep proportional median genes, more highly expressed in T-lep, RR, and L-lep versus ENL. Previously, MMP-9 protein was found to be more highly expressed in T-lep versus L-lep lesions (37), including in Schwann cells (38), and could be induced by M. leprae in cultured Schwann cells (39). In Mycobacterium marinum infection of zebrafish, studied as a model for human tuberculosis, MMP-9 has been shown to be required for granuloma formation (40).…”

Therapeutic failure in American cutaneous leishmaniasis is associated with gelatinase activity and cytokine expression

“…In leprosy, tuberculoid lesions are associated with high levels of TNF-a, IFN-g, MMP-2 and MMP-9 mRNA and intense gelatinolytic activity. Conversely, lesions from the opposite immunological pole (lepromatous form) do not exhibit this profile [35]. In cutaneous leishmaniasis caused by L. braziliensis, a mix of cytokine profiles can be found in the lesions.…”

Clinical and Immunological Aspects of Post–Kala-Azar Dermal Leishmaniasis in Bangladesh

“…30 TIMPs are inhibitors of activated MMPs; the ratio of a specific MMP to its TIMP, therefore, reflects the regulatory milieu. 31 Elevated MMP9 and MMP9/ TIMP occur in tissue and serum from leprosy patients with inflammatory reversal reactions and erythema nodosum leprosum. 31 PKDL may be associated with a similar removal of TIMP1 inhibition of MMP9, leading to basement membrane degradation, inflammation, and remodeling.…”

“…31 Elevated MMP9 and MMP9/ TIMP occur in tissue and serum from leprosy patients with inflammatory reversal reactions and erythema nodosum leprosum. 31 PKDL may be associated with a similar removal of TIMP1 inhibition of MMP9, leading to basement membrane degradation, inflammation, and remodeling. MMP9/TIMP1 may provide a serum marker of PKDL and have value for monitoring response to therapy.…”