Myeloid A Disintegrin and Metalloproteinase Domain 10 Deficiency Modulates Atherosclerotic Plaque Composition by Shifting the Balance from Inflammation toward Fibrosis

Abstract

A disintegrin and metalloproteinase domain 10 (ADAM10) is a metalloprotease involved in cleavage of various cell surface molecules, such as adhesion molecules, chemokines, and growth factor receptors. Although we have previously shown an association of ADAM10 expression with atherosclerotic plaque progression, a causal role of ADAM10 in atherosclerosis has not been investigated. Bone marrow from conditional knockout mice lacking Adam10 in the myeloid lineage or from littermate controls was transplanted into lethally irradiated low density lipoprotein receptor Ldlr(-/-) mice on an atherogenic diet. Myeloid Adam10 deficiency did not affect plaque size, but it increased plaque collagen content. Matrix metalloproteinase 9 and 13 expression and matrix metalloproteinase 2 gelatinase activity were significantly impaired in Adam10-deficient macrophages, whereas their capacity to stimulate collagen production was unchanged. Furthermore, relative macrophage content in advanced atherosclerotic lesions was decreased. In vitro, Adam10-deficient macrophages showed reduced migration toward monocyte chemoattractant protein-1 and transmigration through collagen. In addition, Adam10-deficient macrophages displayed increased anti-inflammatory phenotype with elevated IL-10, and reduced production of proinflammatory tumor necrosis factor, IL-12, and nitric oxide in response to lipopolysaccharide. These data suggest a critical role of Adam10 for leukocyte recruitment, inflammatory mediator production, and extracellular matrix degradation. Thereby, myeloid ADAM10 may play a causal role in modulating atherosclerotic plaque stability.

Alamandine abrogates neutrophil degranulation in atherosclerotic mice

“…For instance, the genetic deletion of Mas receptor in C57BL/6 mice resulted in an increased inflammatory response to LPS injection, suggesting a potent anti-inflammatory role of this receptor in acute systemic inflammatory disorders [18]. macrophages) [21][22][23], neutrophils still represent a major source of these toxic compounds within mouse plaques [14], where their activity might degrade the protective collagen in the fibrous cap and increase the risk of plaque rupture. Confirming these results, a recent study using male Sprague-Dawley rats, Balb/c and C57Bl6/J mice with acute lung injury showed that antagonism of the Mas receptor with A779 was able to restore neutrophil infiltration within the lungs [20].…”

Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival

“…Assessment of atherosclerosis lesions was performed as described previously (van der Vorst et al, 2015). …”

Identification of genes expressed in the migrating primitive myeloid lineage of Xenopus laevis

“…ADAM10 has been found to cleave various cell surface molecules, including adhesion molecules, chemokines, and growth factor receptors. ADAM10-deficient macrophages showed reduced migration and extracellular matrix degradation as well as altered IL-10, IL-12, NO, and TNF signaling in mice (van der Vorst et al, 2015). CTSS is a lysosomal cysteine protease that has been implicated as essential in macrophage migration and development by cleavage of Rip1 kinase in mice (Verollet et al, 2011;McComb et al, 2014).…”