Abstract 377: Angiotensin II Drives Murine Ly-6chi Monocyte Trafficking from the Spleen to the Aneuvrismal Aorta Through B Cells

Abstract

Abdominal aortic aneurysm (AAA) is widespread among elderly people and results in progressive expansion and rupture of the aorta with high mortality. AAA is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation. In particular, macrophages initially accumulate within the site of aneurysm. Early depletion of circulating monocytes protects against the disease. Two monocyte subsets with different migratory behaviours and functions have been described in mice, ‘inflammatory’ Ly6C+ monocytes (classical) and ‘patrolling’ Ly6C- monocytes (nonclassical). In this study, we aim to understand and clarify the role of monocyte-derived cells in AAA development. We monitored monocyte mobilisation up to 28 days in a mouse model of inflammatory AAA, which consists of implanting subcutaneous osmotic pumps delivering Angiotensin II (AngII) at a rate of 1000 ng/kg/min into C57BL6 ApoE-/- male mice between 8 and 12 weeks old. We found that AAA initiation is translated by a rapid and temporary mobilisation of classical monocytes at day 3-6 after AngII followed by non classical monocytes at days 7-9. We showed that classical monocytes are mobilized from the spleen, then recruited in the abdominal adventitia of ApoE-/- in response to AngII treatment as monitored through a pulse labelling method, along with an increased proteasic activity at the abdominal vessel wall as seen by fluorescence tomography. Importantly, we found that classical monocyte number positively correlated to stages of AAA. Splenectomy performed prior to AAA initiation prevented classical monocyte mobilization at day 3-6 after AngII and significantly protected against AAA. We found similar results in ApoE-/- Rag2-/- mice reconstituted with B cell-depleted splenocytes and treated with AngII, suggesting that splenic B cells are responsible for early deleterious mobilization of classical monocytes. Taken together, the data show that splenic classical monocytes directly participate to AAA pathology and could be exploited to improve the prognosis of patients harbouring AAA.