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MARK4 (Microtubule Affinity-Regulating Kinase 4)-Dependent Inflammasome Activation Promotes Atherosclerosis-Brief Report.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Clement, Marc 
Chen, Xiao 
Chenoweth, Hannah L 
Thome, Sarah 

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.

Description

Keywords

MARK4, NLRP3, atherosclerosis, bone marrow cells, inflammasome, inflammation, microtubules, Aged, Aged, 80 and over, Animals, Atherosclerosis, Cells, Cultured, Humans, Inflammasomes, Interleukin-18, Male, Mice, Mice, Inbred C57BL, Middle Aged, NLR Family, Pyrin Domain-Containing 3 Protein, Protein Serine-Threonine Kinases, Receptors, LDL

Journal Title

Arterioscler Thromb Vasc Biol

Conference Name

Journal ISSN

1079-5642
1524-4636

Volume Title

39

Publisher

Ovid Technologies (Wolters Kluwer Health)

Rights

All rights reserved
Sponsorship
British Heart Foundation (None)
European Research Council (281164)
British Heart Foundation (CH/10/001/27642)
British Heart Foundation (RG/15/11/31593)
British Heart Foundation (FS/17/5/32531)
British Heart Foundation