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Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis

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Title
Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis
Author(s)
Choi, S; You, S; Kim, D; Choi, SY; Kwon, HM; Kim, HS; Daehee Hwang; Park, YJ; Cho, CS; Kim, WU
Publication Date
2017-03
Journal
JOURNAL OF CLINICAL INVESTIGATION, v.127, no.3, pp.954 - 969
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Abstract
Defective apoptotic death of activated macrophages has been implicated in the pathogenesis of rheumatoid arthritis (RA). However, the molecular signatures defining apoptotic resistance of RA macrophages are not fully understood. Here, global transcriptome profiling of RA macrophages revealed that the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5) critically regulates diverse pathologic processes in synovial macrophages including the cell cycle, apoptosis, and proliferation. Transcriptomic analysis of NFAT5-deficient macrophages revealed the molecular networks defining cell survival and proliferation. Proinflammatory M1-polarizing stimuli and hypoxic conditions were responsible for enhanced NFAT5 expression in RA macrophages. An in vitro functional study demonstrated that NFAT5-deficient macrophages were more susceptible to apoptotic death. Specifically, CCL2 secretion in an NFAT5-dependent fashion bestowed apoptotic resistance to RA macrophages in vitro. Injection of recombinant CCL2 into one of the affected joints of Nfat5+/-mice increased joint destruction and macrophage infiltration, demonstrating the essential role of the NFAT5/CCL2 axis in arthritis progression in vivo. Moreover, after intra-articular injection, NFAT5-deficient macrophages were more susceptible to apoptosis and less efficient at promoting joint destruction than were NFAT5-sufficient macrophages. Thus, NFAT5 regulates macrophage survival by inducing CCL2 secretion. Our results provide evidence that NFAT5 expression in macrophages enhances chronic arthritis by conferring apoptotic resistance to activated macrophages ⓒ The Journal of Clinical Investigation
URI
http://pr.ibs.re.kr/handle/8788114/3551
DOI
10.1172/JCI87880
ISSN
0021-9738
Appears in Collections:
Center for Plant Aging Research (식물 노화·수명 연구단) > Journal Papers (저널논문)
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