Impact of Monocyte Chemoattractant Protein-1 Deficiency on Cerebral Aneurysm Formation

Abstract

Background and Purpose-Recent studies have suggested that chronic inflammation actively participates in cerebral aneurysm (CA) formation. Macrophages accumulate in CA walls and express proinflammatory genes promoting CA progression, but the molecular mechanisms of monocyte/macrophage recruitment into CA walls remain to be elucidated. Methods-Monocyte chemoattractant protein-1 (MCP-1) expression in experimentally induced CAs was assessed by immunohistochemistry and Western blotting. The role of MCP-1 in CA formation was examined by MCP-1 -/-mice and a plasmid DNA encoding a dominant negative mutant of MCP-1 (7ND). MCP-1 expression in human CAs was examined by immunohistochemistry. Results-MCP-1 expression was upregulated in aneurysmal walls at the early stage of CA formation. MCP-1 -/-mice exhibited a significant decrease of CA formation and macrophage accumulation with decreased expression of matrix metalloproteinase-2, -9, and inducible nitric oxide synthase. Immunohistochemistry for the DNA binding form of nuclear factor-kappa B showed nuclear factor-kappa B activation in MCP-1-expressing cells. Blockade of MCP-1 activity by 7ND resulted in the inhibition of CA progression in rats. In human CAs, MCP-1 was also expressed in CA walls. Conclusions-These data suggest that MCP-1 plays a crucial role in CA formation as a major chemoattractant for monocyte/macrophage. MCP-1 expression in CA walls is induced through nuclear factor-kappa B activation. MCP-1 may be a novel therapeutic target of medical treatment preventing CA progression.

Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

“…In addition, the study found increased plasma concentrations of MCP-1 in unruptured aneurysms. [23] This reaffirms the work of Aoki et al [24] who observed increased MCP-1 expression in rat arterial walls. These data indicate that inflammatory cells are being actively recruited to the aneurysm wall as a result of high chemokine levels, further contributing to IA formation and eventual rupture.…”

Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS

“…22 To examine the chronic inflammation in CA walls, we assessed the macrophage infiltration and responsible molecules, VCAM-1 and MCP-1. VCAM-1 was the adhesion molecule responsible for transendothelial migration of macrophages and MCP-1 was a major chemoattractant for macrophages.…”

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“…Especially, in a series of studies, the crucial contribution of a long-lasting 'chronic' inflammation to the pathogenesis of IAs has been demonstrated and thus nowadays IA is considered as a chronic inflammatory disease affecting intracranial arteries. Notably, we and others have revealed involvement of macrophages, which are the most abundant inflammatory cells detected in IA lesions of both human and animal models [1,2], to progression of IAs through regulating inflammatory responses in situ [3,4]. For example, the pharmacological depletion of macrophages [3] and genetic deletion of a chemoattractant for macrophages [3,4], MCP-1, both significantly suppress inflammatory responses in lesions and IA.…”

“…Notably, we and others have revealed involvement of macrophages, which are the most abundant inflammatory cells detected in IA lesions of both human and animal models [1,2], to progression of IAs through regulating inflammatory responses in situ [3,4]. For example, the pharmacological depletion of macrophages [3] and genetic deletion of a chemoattractant for macrophages [3,4], MCP-1, both significantly suppress inflammatory responses in lesions and IA. Thus, a macrophage itself, factors mediating macrophage infiltration or ones functioning in macrophage to evoke inflammation can become a therapeutic target for IAs.…”