Targeting Toll-like Receptor 2 Or CD19 To Ameliorate CaCl₂-induced Abdominal Aortic Aneurysms In Mice

Abdominal aortic aneurysm (AAA), a chronic inflammatory vascular 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 Toll-like receptor (TLR) 2 plays a critical role in the regulation of wound-repairing process after tissue injury caused by the molecules of pathogen-associated molecular patterns and damage-associated molecular patterns. We hypothesized that TLR2 mediated the calcium chloride (CaCl2)-induced development of AAA and that targeting TLR2 would interfere with AAA development in a mouse model of CaCl2-induced AAA. Selectively blocking TLR2 using a TLR2-neutralizing antibody not only protected against the development of AAA, but also caused an established AAA to regress. TLR2-deficient mice failed to develop AAA and had reduced aortic expansion and internal elastic lamina degradation, validating the pathogenic roles of TLR2 in AAA development. The prophylactic and therapeutic effects of blocking TLR2 were accompanied by a significant inhibition of vascular fibrosis and inflammation because targeting TLR2 decreased the expression or activity of?-SMA, matrix metalloproteinase-2/9, several Th1 and Th2 cytokines, and transcription factor Stat3 in the vascular tissue of AAA. Targeting TLR2 also specifically decreased the expression and extracellular distribution of TLR2 and its endogenous ligands, including high-mobility group box 1, heat shock protein 70, and S100A8, which diminished chronic inflammation and vascular remodeling in the aortic tissue of AAA. In conclusion, our studies define a novel pathway in which the interactions between TLR2 and its endogenous ligands contribute to the pathogenesis of CaCl2-induced AAA and that targeting TLR2 offers great potential toward the development of therapeutic agents against AAA.Abundant researches suggest that in addition to T cells, human AAAs demonstrate large numbers of B lymphocytes, plasma cells, large amounts of immunoglobulin protein within the outer media and adventitia. This suggests that a humoral (auto) immune response is also involved in the occurrence of AAAs. CD19, which is a critical cell-surface signal transduction molecule of B cells, is a most potent positive regulator and critical for humoral immune responses, autoimmunity, and cytokine production. So we investigated the role of CD19 in the development of AAAs. Our results validated that disturbing signal transduction of B cell with anti-CD19 mAbs ameliorates CaCl2-induced abdominal aortic aneurysms in mice. The studies indicate CD19 regulated vascular remodeling and inflammation of AAAs, inhibited fibrogenic cytokine production and antibody production by B cells mainly dependent on TLRs signaling, which was activated by HMGB1 and S100A8, the endogenous TLRs ligand that is up-regulated after CaCl2 injury.Our studies will not only provide insight into the pathogenesis of AAAs but may also lead to the development of novel therapeutic targets, such as TLR2 and CD19.