Deletion of the Mouse Meprin β Metalloprotease Gene Diminishes the Ability of Leukocytes to Disseminate through Extracellular Matrix

Abstract

Meprins are metalloendopeptidases expressed by leukocytes in the lamina propria of the human inflamed bowel, that degrade extracellular matrix proteins in vitro implicating them in leukocyte transmigration events. The aims of these studies were to 1) examine the expression of meprins in the mouse mesenteric lymph node, 2) determine whether macrophages express meprins, and 3) determine whether deletion of the meprin β gene (Mep-1β) mitigated the ability of leukocytes to disseminate through extracellular matrix in vitro. These studies show that meprin α and β are expressed in leukocytes of the mouse mesenteric lymph node, and meprin α, but not β, decreased during intestinal inflammation. Deletion of Mep-1β gene decreased the ability of leukocytes to migrate through matrigel compared with wild-type leukocytes. Meprin β, but not α, was detected in cortical and medullary macrophages of the lymph node. Thus overall, meprin β is expressed by leukocytes in the draining lymph node of the intestine, regardless of the inflammatory status of the animal, and is likely to contribute to leukocyte transmigration events important to intestinal immune responses. Thus, the expression of meprins by leukocytes of the intestinal immune system may have important implications for diseases such as inflammatory bowel diseases, which are aggravated by leukocyte infiltration.

Compartmentalised expression of meprin in small intestinal mucosa: enhanced expression in lamina propria in coeliac disease

“…Meprin also cleaves components of the basement membrane in vitro, such as laminin 1 and 5, nidogen and collagen IV (Kaushal et al, 1994;Walker et al, 1998;Kö hler et al, 2000). The latter activity implicates meprin in cell migration through the basement membrane, a hypothesis that is supported by the observation that leukocytes isolated from mesenteric lymph nodes of meprin b-deficient mice displayed reduced migratory capacity through Matrigel (Crisman et al, 2004). Transmigration through the basement membrane is particularly important for intraepithelial lymphocytes, which are present in increased numbers in coeliac disease (Marsh, 1992;Halstensen and Brandtzaeg, 1993;Jabri et al, 2000).…”

“…However, we previously detected meprin a and meprin b in a subset of CD45-positive lamina propria leukocytes isolated from surgical specimens of the normal human ileum (Lottaz et al, 1999a). Meprin b was also detected in leukocytes from mesenteric lymph nodes, as well as in lamina propria macrophages in mice (Crisman et al, 2004). In contrast to the lamina propria, epithelial meprin mRNA at the mucosal surface was reduced in coeliac disease compared to control mucosa.…”

“…It remains to be seen whether meprin aggravates or dampens inflammation overall. For this purpose, use of meprin-deficient mice in animal models of mucosal inflammation may prove very helpful (Crisman et al, 2004). Ultimately, determination of the biological function of meprin in the intestinal mucosa depends on identification of the relevant substrates in the gut lumen and within the lamina propria.…”

Intersubunit and Domain Interactions of the Meprin B Metalloproteinase

“…They are either secreted from or localized to the brush border membranes of kidney and intestinal epithelial cells of humans and rodents and are expressed by leukocytes and cancer cells under some conditions (3,4). Meprins cleave cytokines, growth factors, bioactive peptides, hormones, and extracellular matrix proteins and have been implicated in inflammatory intestinal disease and in cancer metastases (3)(4)(5).…”

A Comparison of the Binding Sites of Matrix Metalloproteinases and Tumor Necrosis Factor-α Converting Enzyme: Implications for Selectivity

“…1 Meprins are found in mammalian epithelial cells in the kidneys and the intestine. 6 In contrast to other metzincins, the latent homooligomeric meprin complexes can move through extracellular spaces and only become activated at sites where relevant proteases are present. 7 Several MMPs and TACE (ADAM-17) are best-characterized human metzincins.…”