Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis
Susanna Choi, … , Chul-Soo Cho, Wan-Uk Kim
Susanna Choi, … , Chul-Soo Cho, Wan-Uk Kim
Published February 13, 2017
Citation Information: J Clin Invest. 2017;127(3):954-969. https://doi.org/10.1172/JCI87880.
View: Text | PDF
Research Article Immunology Inflammation

Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis

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.

Authors

Susanna Choi, Sungyong You, Donghyun Kim, Soo Youn Choi, H. Moo Kwon, Hyun-Sook Kim, Daehee Hwang, Yune-Jung Park, Chul-Soo Cho, Wan-Uk Kim

×

Figure 2

Induction of NFAT5 expression in macrophages by M1 polarizing and hypoxic stimuli.

Options: View larger image (or click on image) Download as PowerPoint
Induction of NFAT5 expression in macrophages by M1 polarizing and hypoxi...
(A) Increase in NFAT5 expression by IL-1β, M-CSF, and CoCl2. Peripheral blood CD14+ cells from healthy controls were stimulated with M-CSF (20 ng/ml), IL-1β (10 ng/ml), or TNF-α (10 ng/ml) for 48 hours. CoCl2 was treated again for 6 hours after stimulation with M-CSF. NFAT5 expression was determined by Western blot and flow cytometric analyses. Data represent the mean ± SD and are representative of 3 independent experiments. *P < 0.05 versus media only, by Mann-Whitney U test. (B) Increase in NFAT5 expression by M1-polarizing stimuli. Normal peripheral monocytes (CD14+ cells) were stimulated with M-CSF (20 ng/ml) for 48 hours and then stimulated again with IL-4 (20 ng/ml) or IFN-γ (20 ng/ml) plus LPS (100 ng/ml). NFAT5 expression was determined by Western blot analysis. Data represent the mean ± SD of 3 independent experiments. *P < 0.05 versus M-CSF only, by Mann-Whitney U test. (C and D) Hypoxia-induced increase in NFAT5 expression in RA synovial macrophages. CD14+ macrophages were freshly isolated from RA-SF and stimulated with CoCl2 or in the hypoxia chamber (O2 <1%). NFAT5 expression was determined by Western blot analysis (C) after 24 hours and flow cytometric analysis (D) after 6 hours. Data are representative of 3 separate experiments.