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.

NFAT5 Has a Job in the Brain

“…In macrophages (MΦs), NFAT5 mediated its activation, migration, and homeostatic regulatory function [50-52]. A high-salt diet stimulated the accumulation of MΦs in the skin, and MΦs regulated tegmental Na + Clearance in the interstitium via the function of VEGFC/ VEGFR3 and transports of Na + by stimulating the activation of NFAT5.…”

“…In several pathologic conditions, NFAT5 exacerbated the formation of damage regions. A lack of NFAT5 retarded the pathogenesis of atherosclerosis by declining the accumulation of MΦs in atherosclerotic lesions [54], and reduced the severity of arthritis with impaired inflammatory cell infiltration by inhibiting the secretion of C-C motif ligand 2 (CCL2) [50], joint destruction, and synovial hyperplasia [55]. NFAT5 also affected cancer proliferation and metastasis by enhancing protumor MΦ2 differentiation [56].…”

“…CDK5, c-Abl, and ATM promote the nuclear localization of NFAT5, and, in contrast, CK1 inhibits its nuclear accumulation [19]. There are many other factors that influence the activation and expression of NFAT5, such as inflammatory cytokines [16, 77], microRNAs [50, 62, 78, 79], and transcription factors [80-83]. …”

New Insights into Aging Process with a Focus on Cell Morphology, Autophagy and Role of Macrophages and NFAT

“…In contrast, it has been reported that Mac1 + cells are increased in bone marrow in old mice. Others have reported no difference in number, size, or Mac1 expression during macrophage maturation in old mice [36]. Further investigation of the impact of ageing on macrophage differentiation is needed in light of the recent advances in understanding of macrophage differentiation.…”

Macrophages and Inflammation

“…Furthermore, steroid induce the M2 state, and DMARDs such as methotrexate and leflunomide induce M2 state as well; moreover, they impede cell replication and recruitment of immature and inflammatory monocytes to the sites of inflammation [34]. Recently, Choi and colleagues [35] reported that proinflammatory M1-polarizing stimuli and hypoxic conditions induces nuclear factor of activated T-cells 5 (NFAT 5) expression so that enhances chronic arthritis by conferring apoptotic resistance to activated macrophages. Recent animal study reported the therapeutic efficacy in rheumatoid arthritis by targeting macrophage polarization by systemic delivery of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs).…”