NFAT5, which protects against hypertonicity, is activated by that stress via structuring of its intrinsically disordered domain

Kumar, Raj; DuMond, Jenna F.; Khan, Shahjahan; Thompson, E. Brad; He, Yi; Burg, Maurice B.; Ferraris, Joan D.

doi:10.1073/pnas.1911680117

Cited by 18 publications

(7 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S5a). The nuclear factor of activated T‑cells 5 (NFAT5) is an osmotic sensitive transcription factor mediating the expression of genes involved in cell survival under hypertonic conditions [ 44 ]. KRN5, an inhibitor of NFAT5, abolished hyperosmolarity-induced IL-20, suggesting that NFAT5 mediates IL-20 upregulation under hyperosmotic stress conditions (Fig.…”

Section: Resultsmentioning

confidence: 99%

Interleukin-20 is involved in dry eye disease and is a potential therapeutic target

et al. 2022

View full text Add to dashboard Cite

Background Dry eye disease (DED) is a common disease in ophthalmology, affecting millions of people worldwide. Recent studies have shown that inflammation is the core mechanism of DED. IL-20 is a proinflammatory cytokine involved in various inflammatory diseases. Therefore, we aimed to explore the role of this cytokine in the pathogenesis of DED and evaluate the therapeutic potential of the anti-IL-20 monoclonal antibody (mAb) 7E for DED treatment. Methods Clinical tear samples from patients with DED and non-DED controls were collected and their IL-20 protein levels were determined. We established three DED animal models to explore the role of IL-20 and the efficacy of IL-20 antibody in DED. Benzalkonium chloride (BAC)-induced over-evaporative DED, extra-orbital lacrimal gland excision (LGE)-induced aqueous tear-deficient DED, and desiccating stress (DS)-induced combined over-evaporative and aqueous tear-deficient DED animal models were established to investigate the role of IL-20. The anti-IL-20 antibody 7E was established to neutralize IL-20 activity. The effects of IL-20 or 7E on human corneal epithelial cells and macrophages under hyperosmotic stress were analyzed. 7E was topically applied to eyes to evaluate the therapeutic effects in the DED animal models. Results IL-20 was significantly upregulated in the tears of patients with DED and in the tears and corneas of DED animal models. Under hyperosmotic stress, IL-20 expression was induced via NFAT5 activation in corneal epithelial cells. 7E suppressed hyperosmotic stress-induced activation of macrophages. IL-20 induced cell death in corneal epithelial cells and 7E protected cells from hyperosmotic stress-induced cell death. Blocking IL-20 signaling with 7E protected mice from BAC-induced, LGE-induced, and DS-induced DED by reducing DED symptoms and inhibiting inflammatory responses, macrophage infiltration, apoptosis, and Th17 populations in the conjunctiva and draining lymph nodes. Conclusions Our results demonstrated the functions of IL-20 in DED and presented a potential therapeutic option for this condition. Graphical Abstract

show abstract

Section: Resultsmentioning

confidence: 99%

Interleukin-20 is involved in dry eye disease and is a potential therapeutic target

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Importantly, Ser112 is in a disordered region that cannot form enough favorable intra-chain interactions to fold spontaneously but has the energetic capability to gain structure by interacting with co-regulatory proteins. Such coregulatory proteins have been reported as critical for initiating and maintaining transcriptional activity ( 23 ). Also, it is important to note that the phosphorylation level of NFAT5 may play a role in its activity.…”

Section: Resultsmentioning

confidence: 99%

Not enough by half: NFAT5 haploinsufficiency in two patients with Epstein-Barr virus susceptibility

Lopez-Rivera

Castaño-Jaramillo²,

Yamazaki‐Nakashimada³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

IntroductionThe transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals.ObjectiveWe aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology.MethodsAfter informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells.ResultsWe describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis.DiscussionNFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.

show abstract

“…As the high salt-mediated inflammatory phenotype switch of CD4+T cells suggested a tonicity-mediated change, we tested if the tonicity specific transcription factor TonEBP/NFAT-5, a known transcription factor to induce cellular changes following osmotonic stress [ 23 , 33 , 34 , 35 ], played a role in this CD4+T cell differentiation. As shown in Figure 7 A,B, there was the highest increase in NFAT5 expression by day 21 following the third high salt stimulation cycle.…”

Section: Resultsmentioning

confidence: 99%

Ex Vivo High Salt Activated Tumor-Primed CD4+T Lymphocytes Exert a Potent Anti-Cancer Response

Tiriveedhi

Ivy

Myles

et al. 2021

Cancers

View full text Add to dashboard Cite

Cell based immunotherapy is rapidly emerging as a promising cancer treatment. A modest increase in salt (sodium chloride) concentration in immune cell cultures is known to induce inflammatory phenotypic differentiation. In our current study, we analyzed the ability of salt treatment to induce ex vivo expansion of tumor-primed CD4 (cluster of differentiation 4)+T cells to an effector phenotype. CD4+T cells were isolated using immunomagnetic beads from draining lymph nodes and spleens from tumor bearing C57Bl/6 mice, 28 days post-injection of Py230 syngeneic breast cancer cells. CD4+T cells from non-tumor bearing mice were isolated from splenocytes of 12-week-old C57Bl/6 mice. These CD4+T cells were expanded ex vivo with five stimulation cycles, and each cycle comprised of treatment with high salt (Δ0.035 M NaCl) or equimolar mannitol controls along with anti-CD3/CD28 monoclonal antibodies for the first 3 days, followed by the addition of interleukin (IL)-2/IL-7 cytokines and heat killed Py230 for 4 days. Ex vivo high salt treatment induced a two-fold higher Th1 (T helper type 1) expansion and four-fold higher Th17 expansion compared to equimolar mannitol treatment. Importantly, the high salt expanded CD4+T cells retained tumor-specificity, as demonstrated by higher in vitro cytotoxicity against Py230 breast cancer cells and reduced in vivo syngeneic tumor growth. Metabolic studies revealed that high salt treatment enhanced the glycolytic reserve and basal mitochondrial oxidation of CD4+T cells, suggesting a role of high salt in enhanced pro-growth anabolic metabolism needed for inflammatory differentiation. Mechanistic studies demonstrated that the high salt induced switch to the effector phenotype was mediated by tonicity-dependent transcription factor, TonEBP/NFAT5. Using a transgenic murine model, we demonstrated that CD4 specific TonEBP/NFAT5 knock out (CD4cre/creNFAT5flox/flox) abrogated the induction of the effector phenotype and anti-tumor efficiency of CD4+T cells following high salt treatment. Taken together, our data suggest that high salt-mediated ex vivo expansion of tumor-primed CD4+T cells could induce effective tumor specific anti-cancer responses, which may have a novel cell-based cancer immunotherapeutic application.

show abstract

NFAT5, which protects against hypertonicity, is activated by that stress via structuring of its intrinsically disordered domain

Cited by 18 publications

References 80 publications

Interleukin-20 is involved in dry eye disease and is a potential therapeutic target

Interleukin-20 is involved in dry eye disease and is a potential therapeutic target

Not enough by half: NFAT5 haploinsufficiency in two patients with Epstein-Barr virus susceptibility

Ex Vivo High Salt Activated Tumor-Primed CD4+T Lymphocytes Exert a Potent Anti-Cancer Response

Contact Info

Product

Resources

About