Abstract 428: Regression of Abdominal Aortic Aneurysms by Targeting Toll-Like Receptor 2
Abdominal aortic aneurysm (AAA), a chronic inflammatory disorder, results in progressive expansion and rupture of the aorta with high mortality among elderly people. There is increasing evidence that both innate and adaptive immunity tightly regulate the progress of AAA. We recently find that TLR2 plays a critical role in the regulation of wound-repairing process after tissue injury caused by the molecules of pathogen-associated molecular pattern or damage-associated molecular pattern. We wondered if TLR2 had a role in mediating calcium-induced inflammatory responses to participate in the development of AAA in a mice model of CaCl2-induced AAA. We found that selectively blocking TLR2 activity using a TLR2-neutralizing antibody not only prevented the development of AAA but also caused regression of well established AAA elicited by incubation of calcium. Furthermore, TLR2 deficient mice failed to develop AAA and had reduced aortic expansion and internal elastic lamina degradation, validating the roles of TLR2 in the development of AAA. The prophylactic and therapeutic effects of blocking TLR2 activity were accompanied by a significant inhibition of vascular fibrosis and inflammation because targeting TLR2 decreased the expressions of α-SMA, matrix metalloproteinase-2/9, and several Th1 and Th2 cytokines such as IFNγ, IL-10, IL-6, TGFβ1 as well as transcription factor Stat3/p-Stat3 in the vascular tissue of AAA. Targeting TLR2 also specifically decreased the expression and extracellular distribution of high-mobility group box 1 and heat shock protein 70, the endogenous TLR2 ligands that sustain chronic inflammation and vascular injury, in the aortic tissue of AAA. In conclusion, our studies demonstrate that TLR2 plays a critical role in the pathogenesis of calcium-induced AAA and highlight unifying mechanisms that blocking TLR2 activity can inhibit specific immune responses induced by calcium and subsequently by HMGB1/HSP70 to modify injury-induced abnormal vascular remodeling. TLR2 is a promising therapeutic target for the prevention and treatment of AAA.