Matrix Metalloproteinase MMP-12 Promotes Macrophage Transmigration Across Intestinal Epithelial Tight Junctions and Increases Severity of Experimental Colitis

Abstract

Background and Aims Matrix Metalloproteinases (MMPs) play an important role in extracellular matrix regulation during cell growth and wound healing. Increased expression of MMP-12 (human macrophage elastase) has been reported in inflammatory bowel disease (IBD) which is characterized by the loss of epithelial tight junction (TJ) barrier function and an excessive inflammatory response. The aim of this study was to investigate the role of MMP-12 in intestinal TJ barrier function and inflammation. Methods Wild type (WT) and MMP-12 -/- mice were subjected to experimental acute or chronic dextran sodium sulfate (DSS) colitis. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon and ex vivo by Ussing chamber studies. Results DSS administration increased colonic permeability through modulation of TJ proteins and also increased MMP-12 expression in the colonic mucosa of WT mice. The acute as well as chronic DSS-induced increase in colonic TJ permeability and the severity of DSS colitis was found to be markedly attenuated in MMP-12 -/- mice. The resistance of MMP-12 -/- mice to DSS colitis was characterized by reduced macrophage infiltration and transmigration, and reduced basement membrane laminin degradation. Further in vitro and in vivo studies show that macrophage transmigration across epithelial layer is MMP-12 dependent and the epithelial TJ barrier is compromised during macrophage transmigration. Together, this data demonstrates that MMP-12-mediated degradation of basement membrane laminin, macrophage transmigration, and associated loss of intestinal TJ barrier are key pathogenic factors for intestinal inflammation.

Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis

“…Exactly how MMP12 contributes to MMT is not known. Apart from the elastase activity, MMP12 is capable of degrading some proinflammatory mediators such as pro-TNFα [ 34 ], IFNγ [ 35 ] and CXC and CC chemokines [ 36 ]. The removal of these proinflammatory cytokines by MMP12 from the microenvironment of macrophages may promote their differentiation towards M2-like wound healing and pro-fibrotic phenotype.…”

Leaky Gut: Effect of Dietary Fiber and Fats on Microbiome and Intestinal Barrier

“…Restoration of epithelial barrier function by anti-TNF therapy may reflect mucosal healing in the setting of a dampened immune system; however, pre-clinical studies have shown that TNF signaling also modulates TJ. Many studies have shown decreased levels of intestinal TJ-consisting proteins in animal models of IBD [ 40 ], obesity, and T2D [ 41 , 42 ], with increased permeability, suggesting that a leaky pathway is responsible for LGS.…”

“…Sci. 2021, 22, x 4 of 17 of IBD [40], obesity, and T2D [41,42], with increased permeability, suggesting that a leaky pathway is responsible for LGS. Epithelial cells bind each other with tight junction, adherens junction, and desmosome.…”

Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma

“…MMP12 is an elastolytic MMP and capable of degrading extracellular matrix components (Chelluboina et al, 2018). MMP12 plays a pivotal role in inflammatory diseases, such as colitis (Nighot et al, 2021) and chronic obstructive pulmonary disease (Baggio et al, 2020). In addition, MMP12 has been regarded as a potential prognostic biomarker for ovarian cancer (Guo et al, 2020) and gallbladder cancer (Zhao et al, 2019).…”