Marc Clement1, Xiao Chen2, Hannah L Chenoweth1, Zhongzhao Teng3, Sarah Thome1, Stephen A Newland1, James Harrison1, Xian Yu1, Alison J Finigan1, Ziad Mallat1,4, Xuan Li1. 1. From the Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (M.C., H.L.C., S.T., S.A.N., J.H., X.Y., A.J.F., Z.M., X.L.). 2. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China (X.C.). 3. Department of Radiology, University of Cambridge, United Kingdom (Z.T.). 4. Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, France (Z.M.).
Abstract
OBJECTIVE: MARK4 (microtubule affinity-regulating kinase 4) regulates NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome activation. The aim of the study is to examine the role of MARK4 in hematopoietic cells during atherosclerosis. METHODS AND RESULTS: We show increased MARK4 expression in human atherosclerotic lesions compared with adjacent areas. MARK4 is coexpressed with NLRP3, and they colocalize in areas enriched in CD68-positive but α-SMA (α-smooth muscle actin)-negative cells. Expression of MARK4 and NLRP3 in the atherosclerotic lesions is associated with the production of active IL (interleukin)-1β and IL-18. To directly assess the role of hematopoietic MARK4 in NLRP3 inflammasome activation and atherosclerotic plaque formation, Ldlr (low-density lipoprotein receptor)-deficient mice were lethally irradiated and reconstituted with either wild-type or Mark4-deficient bone marrow cells, and were subsequently fed a high-fat diet and cholesterol diet for 9 weeks. Mark4 deficiency in bone marrow cells led to a significant reduction of lesion size, together with decreased circulating levels of IL-18 and IFN-γ (interferon-γ). Furthermore, Mark4 deficiency in primary murine bone marrow-derived macrophages prevented cholesterol crystal-induced NLRP3 inflammasome activation, as revealed by reduced caspase-1 activity together with reduced production of IL-1β and IL-18. CONCLUSIONS: MARK4-dependent NLRP3 inflammasome activation in the hematopoietic cells regulates the development of atherosclerosis.
OBJECTIVE:MARK4 (microtubule affinity-regulating kinase 4) regulates NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome activation. The aim of the study is to examine the role of MARK4 in hematopoietic cells during atherosclerosis. METHODS AND RESULTS: We show increased MARK4 expression in humanatherosclerotic lesions compared with adjacent areas. MARK4 is coexpressed with NLRP3, and they colocalize in areas enriched in CD68-positive but α-SMA (α-smooth muscle actin)-negative cells. Expression of MARK4 and NLRP3 in the atherosclerotic lesions is associated with the production of active IL (interleukin)-1β and IL-18. To directly assess the role of hematopoietic MARK4 in NLRP3 inflammasome activation and atherosclerotic plaque formation, Ldlr (low-density lipoprotein receptor)-deficient mice were lethally irradiated and reconstituted with either wild-type or Mark4-deficient bone marrow cells, and were subsequently fed a high-fat diet and cholesterol diet for 9 weeks. Mark4deficiency in bone marrow cells led to a significant reduction of lesion size, together with decreased circulating levels of IL-18 and IFN-γ (interferon-γ). Furthermore, Mark4deficiency in primary murine bone marrow-derived macrophages prevented cholesterol crystal-induced NLRP3 inflammasome activation, as revealed by reduced caspase-1 activity together with reduced production of IL-1β and IL-18. CONCLUSIONS:MARK4-dependent NLRP3 inflammasome activation in the hematopoietic cells regulates the development of atherosclerosis.
Entities:
Keywords:
MARK4; NLRP3; atherosclerosis; bone marrow cells; inflammasome; inflammation; microtubules