NFAT5 Deficiency Alleviates Formalin-Induced Inflammatory Pain Through mTOR

• Published in: International journal of molecular sciences 2021-03, Vol.22 (5), p.2587
• Main Authors: Gwon, Do Hyeong, Kim, Song I, Lee, Seoung Hun, Noh, Chan, Kim, Yeojung, Yun, Sangwon, Lee, Won Hyung, Oh, Jun Young, Kim, Dong Woon, Hong, Jinpyo, Lee, Sun Yeul
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Arthritis; Behavior; c-Fos; c-Fos protein; Cell Line, Tumor; Cytokines; ERK; Extracellular signal-regulated kinase; Formaldehyde - pharmacology; Gene expression; Glutamic acid receptors; Inflammation; Inflammation - metabolism; inflammatory pain; Investigations; Kinases; Lymphocytes; Male; Mice; Mice, Inbred C57BL; mTOR; N-Methyl-D-aspartic acid receptors; Neurons; Neurons - metabolism; NF-AT protein; NFAT5; NR2B; Osmotic stress; Pain; Pain - chemically induced; Pain - metabolism; Pain Measurement - methods; PC12 Cells; Pheochromocytoma cells; Phosphorylation; Physiology; Proteins; Rapamycin; Rats; Spinal Cord - metabolism; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription factors; Transcription Factors - metabolism; Up-Regulation - physiology
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22052587

Nuclear factor of activated T cells (NFAT5) is a well-known transcription factor that regulates the expression of genes involved in osmotic stress. However, the role of NFAT5 in inflammatory pain remains unknown. Here, we studied the function of NFAT5 in inflammatory pain using NFAT5-heterozygous (Het) mice. To study inflammatory pain, we injected 10 µL of 2% formalin into the right hind paws of mice and monitored pain behaviors, such as licking, lifting, and flinching, for 60 min. After the first 15 min (phase I), there were no significant differences in pain behaviors between wild-type (WT) and NFAT5-Het mice. However, from 15-60 min (phase II), NFAT5-Het mice displayed significantly fewer pain behaviors compared to WT mice. Further, the expression levels of inflammatory-pain-related factors, including c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated -methyl-D-aspartate receptor subunit 2B (p-NR2B), were significantly elevated in the spinal dorsal neurons of formalin-treated WT mice but was not elevated in NFAT5-Het mice. Similarly, c-Fos, p-ERK, and p-NR2B levels were significantly higher in glutamate-treated PC12 neuronal cells but were not affected by Nfat5 silencing in glutamate-treated PC12 cells. Altogether, our findings suggest that NFAT5 deficiency may mitigate formalin-induced inflammatory pain by upregulating mammalian target of rapamycin (mTOR) expression and downregulating its downstream factors in spinal dorsal neurons. Therefore, NFAT5 is a potential therapeutic target for the treatment of inflammatory pain.