Susanna Choi,1 Sungyong You,2 Donghyun Kim,1 Soo Youn Choi,3 H. Moo Kwon,3 Hyun-Sook Kim,4 Daehee Hwang,5 Yune-Jung Park,1,6 Chul-Soo Cho,1,6 and Wan-Uk Kim1,6,*
1Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, Republic of Korea. 2Department of Surgery and Biomedical Sciences, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, California, USA. 3School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea. 4Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Republic of Korea. 5Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea. 6Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
*Address correspondence to: Wan-Uk Kim, Department of Internal Medicine, Division of Rheumatology, The Catholic University of Korea, School of Medicine, Seoul, 137-701, Republic of Korea
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.