Abstract
Toll-like receptor (TLR) family plays a key role in innate immunity and various inflammatory responses. TLR4, one of the well-characterized pattern-recognition receptors, can be activated by endogenous damage-associated molecular pattern molecules such as high mobility group box 1 (HMGB1) to sustain sterile inflammation. Evidence suggested that blockade of TLR4 signaling may confer protection against abdominal aortic aneurysm (AAA). Herein we aimed to obtain further insight into the mechanism by which TLR4 might promote aneurysm formation. Characterization of the CaCl2-induced AAA model in mice revealed that upregulation of TLR4 expression, localized predominantly to vascular smooth muscle cells (VSMCs), was followed by a late decline during a 28-day period of AAA development. In vitro, TLR4 expression was increased in VSMCs treated with HMGB1. Knockdown of TLR4 by siRNA attenuated HMGB1-enhanced production of proinflammatory cytokines, specifically interleukin-6 and monocyte chemoattractant protein-1 (MCP-1), and matrix-degrading matrix metalloproteinase (MMP)-2 from VSMCs. In vivo, two different strains of TLR4-deficient (C57BL/10ScNJ and C3H/HeJ) mice were resistant to CaCl2-induced AAA formation compared to their respective controls (C57BL/10ScSnJ and C3H/HeN). Knockout of TLR4 reduced interleukin-6 and MCP-1 levels and HMGB1 expression, attenuated macrophage accumulation, and eventually suppressed MMP production, elastin destruction and VSMC loss. Finally, human AAA exhibited higher TLR4 expression that was localized to VSMCs. These data suggest that TLR4 signaling contributes to AAA formation by promoting a proinflammatory status of VSMCs and by inducing proteinase release from VSMCs during aneurysm initiation and development.
Highlights
Toll-like receptors (TLRs) are type I transmembrane proteins that play a key role in innate immunity and various inflammatory responses
Despite the pronounced attenuation of AngII-infusion abdominal aortic aneurysm (AAA) formation in mice with whole body TLR4 deficiency, repopulation with TLR4-deficient bone marrow-derived cells in lethally irradiated low-density lipoprotein receptor (LDLR)-deficient mice exhibited no effects on AAA formation, suggesting that TLR4 exerted its action on AAA through nonhematopoietic cells [22]
While our study was being prepared for publication, a recent study reported that AngII-induced TLR4-mediated AAA in apolipoprotein E-knockout mice is dependent on STAT3 [36]
Summary
Toll-like receptors (TLRs) are type I transmembrane proteins that play a key role in innate immunity and various inflammatory responses. Activation of TLRs and downstream signaling has important physiological, immunological and pathological significance [1,2,3,4,5,6]. TLR4, one of the most extensively characterized pattern-recognition receptors (PRRs), is the receptor for lipopolysaccharide derived from gram-negative bacteria. TLR4 can be activated by endogenous damage-associated molecular pattern molecules (DAMPs, e.g., high mobility group box 1 [HMGB1] and S100 family) [2,3,6,7]. Endogenous ligand-TLR4 interaction may initiate positive feedback loops where increasing tissue damage perpetuates proinflammatory responses [3,8]. Recent findings have revealed a previously unappreciated involvement of TLR4 in sterile inflammation among a variety of cardiovascular diseases such as myocardial ischemia-reperfusion injury and stroke [1,2,4,5,9,10,11]
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