Prevention of CaCl₂-induced aortic inflammation and subsequent aneurysm formation by the CCL3-CCR5 axis

Inflammatory mediators such as cytokines and chemokines are crucially involved in the development of abdominal aortic aneurysm (AAA). Here we report that CaCl₂ application into abdominal aorta induces AAA with intra-aortic infiltration of macrophages as well as enhanced expression of chemokine (C-C motif) ligand 3 (CCL3) and MMP-9. Moreover, infiltrating macrophages express C-C chemokine receptor 5 (CCR5, a specific receptor for CCL3) and MMP-9. Both Ccl3^-/- mice and Ccr5^-/- but not Ccr1^-/- mice exhibit exaggerated CaCl₂-inducced AAA with augmented macrophage infiltration and MMP-9 expression. Similar observations are also obtained on an angiotensin II-induced AAA model. Immunoneutralization of CCL3 mimics the phenotypes observed in CaCl₂-treated Ccl3^-/- mice. On the contrary, CCL3 treatment attenuates CaCl₂-induced AAA in both wild-type and Ccl3^-/- mice. Consistently, we find that the CCL3-CCR5 axis suppresses PMA-induced enhancement of MMP-9 expression in macrophages. Thus, CCL3 can be effective to prevent the development of CaCl₂-induced AAA by suppressing MMP-9 expression.