Blocking TNF-α Attenuates Aneurysm Formation in a Murine Model

Abstract

Abdominal aortic aneurysm (AAA) is one of a number of diseases associated with a prominent inflammatory cell infiltrate and local destruction of structural matrix macromolecules. This chronic infiltrate is predominately composed of macrophages and T lymphocytes. Activated macrophages produce a variety of cytokines, including TNF-α. Elevated levels of TNF-α were observed in patients with AAA, suggesting that TNF-α may play a role in the pathogenic mechanisms of AAA. In the present study, we investigated the role of TNF-α in AAA formation. By studying a murine aneurysm model, we found that both mRNA and protein levels of TNF-α were increased in aneurysm tissue compared with normal aortic tissues. Therefore, we tested the response of mice lacking expression of TNF-α. These mice were resistant to aneurysm formation. Our results show that TNF-α deficiency attenuates matrix metalloproteinase (MMP) 2 and MMP-9 expression and macrophage infiltration into the aortic tissue. These data suggest that TNF-α plays a central role in regulating matrix remodeling and inflammation in the aortic wall leading to AAA. In addition, we investigated the pharmacological inhibition of AAA. A Food and Drug Administration-approved TNF-α antagonist, infliximab, inhibited aneurysm growth. Our data also show that infliximab treatment attenuated elastic fiber disruption, macrophage infiltration, and MMP-2 and MMP-9 expression in aortic tissue. This study confirms that a strategy of TNF-α antagonism may be an important therapeutic strategy for treating AAA.

Chemokine (C-X-C Motif) Receptor 4 Blockade by AMD3100 Inhibits Experimental Abdominal Aortic Aneurysm Expansion Through Anti-Inflammatory Effects

“…2,16 Once recruited, inflammatory cells exacerbate local inflammation through the secretion of proinflammatory mediators. 2 Among these inflammatory effectors, monocyte chemotactic protein-1, 21 regulated on activation, normal T-cell expressed and secreted (RANTES), 22 interleukin-1β, 23 interleukin-6, 24 or tumor necrosis factor-α 25 have been clearly implicated in the development of experimental AAAs and are upregulated in human AAA walls. 26 In our study, we show that MCP-1, MIP-1β, MIP-2α, and RANTES mainly produced by macrophages, as well as IL-1β, IL-6, and TNF-α, are overexpressed in the wall of CaCl 2 -induced AAAs.…”

Inhibition of KLF5–Myo9b–RhoA Pathway–Mediated Podosome Formation in Macrophages Ameliorates Abdominal Aortic Aneurysm

“…Thus, to validate these observations, timelapse imaging experiments were performed, and the effects of KLF5 deficiency on forward and backward movement were investigated using chemotaxis assays in culture dishes. Because MCP-1 or TNF-α has been shown to contribute to mouse models of AAA, 21,22 macrophages were seeded in culture dishes, and MCP-1 or TNF-α was added to one side of the culture dish to establish a spatial chemotactic gradient. Although WT macrophages exhibited marked time-dependent migration toward high concentrations of MCP-1 ( Figure 3H and 3I), the movement of myeKlf5 −/− macrophages was minimal ( Figure 3H, 3J, and 3K).…”

Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3

“…[12] In mammals, the JAK/STAT pathway transduces signals for a wide array of cytokines and growth factors including AngII, TNF-α, IL-1β, IL-6 and IFN-γ all of which have been implicated in AAA formation. [13][14][15] Stimulation of IL-6 and IL-1 production by bacterial lipopolysaccharide (LPS), a TLR4 agonist, in a macrophage cell line is decreased after treatment with either a STAT3 inhibitor or after silencing with a STAT3 siRNA consistent with a role for STAT3 in TLR4 signaling. [16] The role of the JAK/STAT pathway in TLR4 signaling and AngII-mediated AAA formation is, however, unclear.…”