NFAT1 Orchestrates Spinal Microglial Transcription and Promotes Microglial Proliferation via c‐MYC Contributing to Nerve Injury‐Induced Neuropathic Pain

Abstract

Peripheral nerve injury‐induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T‐cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2‐mediated DNA demethylation. Global or microglia‐specific deletion of Nfat1 attenuates SNL‐induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia‐related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il‐1b, and c‐Myc in the spinal cord. Microglia‐specific overexpression of c‐MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c‐MYC by intrathecal injection of inhibitor or siRNA alleviates SNL‐induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c‐MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain.

miR‐26a‐5p alleviates CFA‐induced chronic inflammatory hyperalgesia through Wnt5a/CaMKII/NFAT signaling in mice

“…NFAT directly mediates the upregulation of TNFα and IL-1β. 82 Our study also found that after the noncanonical Wnt signaling pathway was inhibited, the levels of IL-1β, IL-6, and TNFα in the spinal cord decreased and at the same time attenuated the neuroinflammation induced by microglia. Furthermore, in the current study, we focused on the status and function of microglia during the inflammatory pain, but neurons also may involve in the analgesia of miR-26a-5p by targeting Wnt5a, which is shown in Figure 3E and still needs further study to investigate the related mechanism of Wnt5a in neurons and neuron-microglia interaction under inflammatory pain background.…”

“…Previous studies have shown that loss of NFAT alters the expression of several genes, including Itgam, Tnf, Il‐1b, and c‐Myc. NFAT directly mediates the upregulation of TNF‐α and IL‐1β 82 . Our study also found that after the noncanonical Wnt signaling pathway was inhibited, the levels of IL‐1β, IL‐6, and TNF‐α in the spinal cord decreased and at the same time attenuated the neuroinflammation induced by microglia.…”

Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization

“…When the cell is in the normal state, NFAT is in a highly phosphorylated state due to the action of the intracellular kinases CK1 and DYRK2 (Putney, 2012). Calcineurin is a serine/ threonine calcium-dependent phosphatase that dephosphorylates and induces the nuclear translocation of NFAT1 (Jiang et al, 2022). When the nervous system is damaged, due to intracellular calcium overload, calcineurin dephosphorylates NFAT to induce its nuclear translocation and transcriptional regulation (Kurauchi et al, 2017;Jiang et al, 2022), including activation of HIF1α (Goyal et al, 2012).…”

“…Calcineurin is a serine/ threonine calcium-dependent phosphatase that dephosphorylates and induces the nuclear translocation of NFAT1 (Jiang et al, 2022). When the nervous system is damaged, due to intracellular calcium overload, calcineurin dephosphorylates NFAT to induce its nuclear translocation and transcriptional regulation (Kurauchi et al, 2017;Jiang et al, 2022), including activation of HIF1α (Goyal et al, 2012). Hypobaric hypoxia at high altitude triggers the expression of HIF1α and inflammatory mediators (Goyal et al, 2012;Ahmad et al, 2013).…”

“…Hypobaric hypoxia at high altitude triggers the expression of HIF1α and inflammatory mediators (Goyal et al, 2012;Ahmad et al, 2013). NFAT1 is the major regulator of immune cell proliferation and microglial differentiation (Jiang et al, 2022). Whether NFAT1 is an upstream regulator in the pathogenesis of HA-TBI and whether NFAT1 regulates the microglial inflammatory (polarization) response after HA-TBI are worth studying.…”