| Autor: |
Clement, Marc, Chen, Xiao, Chenoweth, Hannah L, Teng, Zhongzhao, Thome, Sarah, Newland, Stephen A, Harrison, James, Yu, Xian, Finigan, Alison J, Mallat, Ziad, Li, Xuan |
| Přispěvatelé: |
Teng, Zhongzhao [0000-0003-3973-6157], Harrison, James [0000-0003-4960-5062], Mallat, Ziad [0000-0003-0443-7878], Li, Xuan [0000-0002-0754-3011], Apollo - University of Cambridge Repository |
| Rok vydání: |
2019 |
| Předmět: |
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| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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