MyD88 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Independent of Signaling Through Toll-Like Receptors

Objective—The purpose of this study was to determine whether myeloid differentiation factor 88 (MyD88) and its related Toll-like receptors (TLRs) 2 and 4 contributed to the development of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) and atherosclerosis. Methods and Results—AngII was infused into either apoE Ϫ/Ϫ or LDL receptor (LDLR) Ϫ/Ϫ male mice that were either MyD88 ϩ/ϩ or Ϫ/Ϫ. MyD88 deficiency profoundly reduced AngII-induced AAAs and atherosclerosis in both strains. To define whether deficiency of specific TLRs had similar effects, AngII was infused into LDLR Ϫ/Ϫ mice that were also deficient in either TLR2 or TLR4. TLR2 deficiency had no effect on AAA development but inhibited atherosclerosis. In contrast, TLR4 deficiency attenuated both AAAs and atherosclerosis. To resolve whether MyD88 and TLR4 exerted their effects through cells of hematopoietic lineage, LDLR Ϫ/Ϫ mice were lethally irradiated and repopulated with bone marrow-derived cells from either MyD88 or TLR4 strains. MyD88 deficiency in bone marrow-derived cells profoundly reduced both AngII-induced AAAs and atherosclerosis. However, TLR4 deficiency in bone marrow-derived cells had no effect on either pathology. Conclusion—These studies demonstrate that MyD88 deficiency in leukocytes profoundly reduces AngII-induced AAAs and atherosclerosis via mechanisms independent of either TLR2 or TLR4. A bdominal aortic aneurysms (AAAs) in humans are characterized by permanent dilations that have an increasing propensity to rupture with expansion. Despite the devastating impact of the disease in an increasingly larger number of people, the mechanistic basis for the initiation, progression, and rupture of AAAs has not been defined. Aneurysmal tissues are highly heterogeneous, which is manifested as accumulation of several types of leukocytes, substantial fragmentation of extracellular matrix, and athero-sclerosis. 1 Notably, cells of the innate and adaptive immune systems accumulate in human AAA tissue and have been linked to the development of the disease. 2 Several animal models of AAAs have become widely used to gain insight into mechanisms of the human disease. 3 One of the most commonly used AAA models generates the disease by chronic subcutaneous infusion of angiotensin II (AngII) into mice. 4 AngII infusion promotes aneurysmal disease in both normo-and hypercholesterolemic mice, although AAAs occur more frequently in hypercholesterolemic mice. 5,6 In addition to AAAs, infusion of AngII to hypercho-lesterolemic mice also augments atherosclerosis. 7,8 Like the human disease, AAAs developed during AngII infusion are characterized by progressive leukocyte accumulation, extra-cellular matrix degradation, lumen expansion, thrombus, and atherosclerosis. 4 Both innate and adaptive immunities have proposed …