NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes

Abstract

Macrophages are exquisite sensors of tissue homeostasis that can rapidly switch between pro- and anti-inflammatory or regulatory modes to respond to perturbations in their microenvironment. This functional plasticity involves a precise orchestration of gene expression patterns whose transcriptional regulators have not been fully characterized. We had previously identified the transcription factor NFAT5 as an activator of TLR-induced responses, and in this study we explore its contribution to macrophage functions in different polarization settings. We found that both in classically and alternatively polarized macrophages, NFAT5 enhanced functions associated with a proinflammatory profile such as bactericidal capacity and the ability to promote Th1 polarization over Th2 responses. In this regard, NFAT5 upregulated the Th1-stimulatory cytokine IL-12 in classically activated macrophages, whereas in alternatively polarized ones it enhanced the expression of the pro-Th1 mediators Fizz-1 and arginase 1, indicating that it could promote proinflammatory readiness by regulating independent genes in differently polarized macrophages. Finally, adoptive transfer assays in vivo revealed a reduced antitumor capacity in NFAT5-deficient macrophages against syngeneic Lewis lung carcinoma and ID8 ovarian carcinoma cells, a defect that in the ID8 model was associated with a reduced accumulation of effector CD8 T cells at the tumor site. Altogether, detailed analysis of the effect of NFAT5 in pro- and anti-inflammatory macrophages uncovered its ability to regulate distinct genes under both polarization modes and revealed its predominant role in promoting proinflammatory macrophage functions.

High-salt diet inhibits tumour growth in mice via regulating myeloid-derived suppressor cell differentiation

“…16a-e, the lentivirus (NFAT5-siRNA-LV) could silence NFAT5 expression in M-MDSCs and macrophages, but did not affect NFAT5 in PMN-MDSCs and CD3 + T cells at either the mRNA or protein level. In the tumourbearing mice treated with HSD, NFAT5 silencing in M-MDSCs and macrophages (though adoptively transferred NFAT5deficient macrophages in vivo could weaken antitumour capacity 26 ) could partly restore tumour growth, because PMN-MDSC's function switch affected by HSD could also display Fig. 4 HSD promoted MDSC differentiation and functional transformation.…”

“…As a typical environmental stress sensed by cells, hypertonicity induced by highsalt intake can trigger immune responses in macrophages mediated by transcription factors, such as the tonicity-responsive enhancer-binding protein (NFAT5) 25 . Studies have demonstrated that the p38/NFAT5 axis enhances the expression of a number of pro-inflammatory genes and the survival of macrophages 26,27 . However, whether high-salt intake similarly influences the functions of MDSCs in the body is unknown.…”

The transcription factor NFAT5 limits infection-induced type I interferon responses

“…Previous work has shown that NFAT5 induces diverse pro-inflammatory genes in response to TLRs and classical macrophage polarization (Buxadé et al, 2012; Tellechea et al, 2018). Gene set enrichment analysis (GSEA) of a previously published NFAT5-regulated transcriptome in macrophages stimulated with the TLR4 ligand LPS (Buxadé et al, 2012) identified enhanced expression of ISGs in NFAT5-deficient macrophages (Fig.…”

“…NFAT5 occupies a distinct functional niche in the control of antipathogen responses by attenuating IFN-I gene induction while enhancing expression of other inflammatory mediators (Buxadé et al, 2012; Tellechea et al, 2018). This unique duality is the result of the mechanism through which NFAT5 inhibits IFN-I expression by opposing IRF3, the master transcription factor specialized in IFN-I expression.…”

“…One mechanism by which IFN-I does so is by dampening production of inflammatory cytokines such as IL-1β in macrophages (Guarda et al, 2011). NFAT5 can enhance specific antipathogenic responses in TLR-activated macrophages by promoting expression of pro-inflammatory genes including Il1b (Buxadé et al, 2012; Tellechea et al, 2018), and this capacity could be modulated by its ability to repress IFN-I. Elucidating how NFAT5 affects the interplay between inflammatory and IFN-I responses during overlapping viral and bacterial infections is an open question for future studies.…”