Myeloid Bmal1 deletion increases monocyte recruitment and worsens atherosclerosis

BMAL1, the nonredundant transcription factor in the core molecular clock, has been implicated in cardiometabolic diseases in mice and humans. BMAL1 controls the cyclic trafficking of Ly6c^hi monocytes to sites of acute inflammation. Myeloid deficiency of Bmal1 also worsens chronic inflammation in diet-induced obesity. We studied whether myeloid Bmal1 deletion promotes atherosclerosis by enhancing monocyte recruitment to atherosclerotic lesions. By generating Bmal1FloxP/FloxP;LysMCre mice on the Apoe^-/- background, we showed that Bmal1 deletion in myeloid cells increased the size of atherosclerotic lesions. Bmal1 deficiency in monocytes and macrophages resulted in an increased total number of lesional macrophages in general and Ly6c^hi infiltrating monocyte-macrophages in particular, accompanied by skewed M2 to M1 macrophage phenotype. Ly6c^hi and/or Ly6clo monocyte subsets in blood, spleen, and bone marrow were not altered. Cell tracking and adoptive transfer of Ly6c^hi monocytes showed Bmal1 deficiency induced more trafficking of Ly6c^hi monocytes to atherosclerotic lesions, preferential differentiation of Ly6c^hi monocytes into M1 macrophages, and increased macrophage content and lesion size in the carotid arteries. We demonstrated that Bmal1 deficiency in macrophages promotes atherosclerosis by enhancing recruitment of Ly6c^hi monocytes to atherosclerotic lesions.