Enhanced Expression of Human Metalloelastase (MMP-12) in Cutaneous Granulomas and Macrophage Migration

Abstract

Accumulation of inflammatory cells such as macrophages may lead to degeneration of connective tissue matrix in various skin diseases. Macrophage metalloelastase, is a matrix metalloproteinase (MMP-12) capable of degrading elastin as well as various basement membrane components. To investigate the role of human macrophage metalloelastase in skin, we assessed by in situ hybridization and immunohistochemistry 66 specimens representing skin diseases characterized either by changes in elastic fibers or by pronounced infiltrations of extravasating and migrating macrophages. CD68 immunostaining was performed to identify the human macrophage metalloelastase-positive cells and Weigert's Resorcin-Fuchsin staining to reveal the status of elastic fibers. We found abundant expression of human macrophage metalloelastase mRNA in macrophages in areas devoid of normal elastic fibers in granulomatous skin diseases sarcoidosis, necrobiosis lipoidica diabeticorum, and granuloma annulare. Positive cells for human macrophage metalloelastase protein could be detected in the same regions as well as positive immunostaining for urokinase plasminogen activator. Of the other matrix metalloproteinases capable of degrading elastin, 92 kDa gelatinase colocalized with human macrophage metalloelastase, while 72 kDa gelatinase was produced by surrounding fibroblast-like cells. Furthermore, human macrophage metalloelastase was expressed by macrophages in areas with disrupted basement membrane, as assessed by type IV collagen staining, in pityriasis lichenoides and dermatitis herpetiformis. Specimens of anetoderma, acrodermatitis chronica atrophicans and pseudoxanthoma elasticum showed no signal for human macrophage metalloelastase. Matrilysin was not detected in any of the samples investigated. Our study suggests that human macrophage metalloelastase may contribute to elastin degradation occurring in granulomatous skin diseases and may aid macrophage migration through the epidermal and vascular basement membranes in inflammatory disorders.

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

“…The ability of MMP-12 to cleave off IFN-α receptor 2-binding sites (35) blocks the action of type I IFN, which in previous work we showed blocks antimicrobial responses in leprosy (16). The presence of MMP-12 in T-lep and RR granulomas, as well as other granulomatous diseases such as sarcoidosis (36), suggests that MMP-12 is part of a tissue remodeling and inflammation gene network that contributes to granuloma formation and/or maintenance. The induction of MMP-12 in RR lesions indicates the dynamic upregulation of this protein during the clinical reduction in the bacillary load and gain in immunity.…”

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

“…Since MMP-12 is not only involved in lung tissue remodeling-associated diseases [35,37,41,46,50,[81][82][83][84][85][86][87][88][89], substantial efforts have been made to develop MMP-12 synthetic inhibitors. However, inhibiting a specific MMP is a difficult goal because of the high conservation between many MMPs in terms of overall 3D-structure, topology of the catalytic domain and requirement of specific amino-acid residues in the active site [90,91].…”

Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease

“…Matrix metalloproteinases and TIMPs have previously been implicated in the pathomechanism of several inflammatory disorders of the skin and intestine, such as celiac disease, ulcerative colitis, and Crohn's disease (9,10), as well as granulomatous skin disorders, lichen planus, and scleroderma (11)(12)(13)(14). Several studies have shown the expression of various MMPs, particularly MMPs -1, -3, -12 and -14, in intestinal ulcers of patients with inflammatory bowel disease (9,10,15,16).…”