Human macrophages synthesize type VIII collagenin vitroand in the atherosclerotic plaque

Abstract

Type VIII collagen is a short-chain collagen that is present in increased amounts in atherosclerotic lesions. Although the physiological function of this matrix protein is unclear, recent data suggest an important role in tissue remodeling. Type VIII collagen in the atherosclerotic lesion is mainly derived from smooth muscle cells. We now show that macrophages in the atherosclerotic vessel wall and monocytes in adjacent mural thrombi also express type VIII collagen. We demonstrated this using a novel combined fluorescence technique that simultaneously stains, within the same tissue section, specific RNAs by in situ hybridization and proteins by indirect immunofluorescence. In culture, human monocyte/macrophages expressed type VIII collagen at all time points from 1 h to 3 wk after isolation. Western blotting and immunoprecipitation also revealed secretion of type VIII collagen into the medium of 14-day-old macrophages. Because this is the first report of secretion of a collagen by macrophages, we tested the effect of lipopolysaccharide (LPS) and interferon gamma, substances that stimulate macrophages to secrete lytic enzymes, on macrophage expression of type VIII collagen. LPS and interferon gamma decreased expression of type VIII collagen. By contrast, secretion of matrix metalloproteinase 1 (MMP 1) was increased, indicating a switch from a collagen-producing to a degradative phenotype. Double in situ hybridization studies of expression of type VIII collagen and MMP 1 in human coronary arteries showed that in regions important for plaque stability, the ratio of MMP 1 RNA to macrophage type VIII collagen RNA varies widely, indicating that the transition from one phenotype to the other that we observed in vitro may also occur in vivo.

Macrophage-specific overexpression of group IIa sPLA2 increases atherosclerosis and enhances collagen deposition

“…SMC and fibroblast contents were not changed in sPLA 2 -tp mice, which may indicate that the difference in collagen in the lesions cannot be attributed to an increase in specific cell types producing collagen. The exact source of the collagen remains unclear, but it should be noted that collagen VIII can be produced by macrophages in atherosclerotic lesions (43). More collagen in atherosclerotic lesions can be the result of either increased overall production in the lesion or decreased degradation.…”

Macrophage diversity in renal injury and repair

“…The downstream accumulation of TGF-β-induced ECM is generally considered destructive in nature (63). However, macrophages may synthesize and secrete collagens themselves (64). TGF-β can also deactivate macrophages (65) and induce a tissue-stabilizing, antiinflammatory macrophage phenotype characterized by production of collagen type VI (66).…”

Molecular imaging of the extracellular matrix in the context of atherosclerosis

“…Comparable to elastic fibers, collagen also provides tensile strength to the fibrous cap thereby stabilizing the plaque and reducing the probability of plaque rupture [40]. The overall synthesis of the different types of collagen is increased dramatically after the initiation of atherosclerosis in experimental models and human plaques [41][42][43][44][45]. A strong interaction between collagen, SMCs and macrophages can be observed within the matrix of atherosclerotic lesions [42,46,47].…”