Role of CGRP in Neuroimmune Interaction via NF-κB Signaling Genes in Glial Cells of Trigeminal Ganglia

Abstract

Activation of the trigeminal system causes the release of various neuropeptides, cytokines, and other immune mediators. Calcitonin gene-related peptide (CGRP), which is a potent algogenic mediator, is expressed in the peripheral sensory neurons of trigeminal ganglion (TG). It affects the inflammatory responses and pain sensitivity by modulating the activity of glial cells. The primary aim of this study was to use array analysis to investigate the effect of CGRP on the glial cells of TG in regulating nuclear factor kappa B (NF-κB) signaling genes and to further check if CGRP in the TG can affect neuron-glia activation in the spinal trigeminal nucleus caudalis. The glial cells of TG were stimulated with CGRP or Minocycline (Min) + CGRP. The effect on various genes involved in NF-κB signaling pathway was analyzed compared to no treatment control condition using a PCR array analysis. CGRP, Min + CGRP or saline was directly injected inside the TG and the effect on gene expression of Egr1, Myd88 and Akt1 and protein expression of cleaved Caspase3 (cleav Casp3) in the TG, and c-Fos and glial fibrillary acidic protein (GFAP) in the spinal section containing trigeminal nucleus caudalis was analyzed. Results showed that CGRP stimulation resulted in the modulation of several genes involved in the interleukin 1 signaling pathway and some genes of the tumor necrosis factor pathway. Minocycline pre-treatment resulted in the modulation of several genes in the glial cells, including anti-inflammatory genes, and neuronal activation markers. A mild increase in cleav Casp3 expression in TG and c-Fos and GFAP in the spinal trigeminal nucleus of CGRP injected animals was observed. These data provide evidence that glial cells can participate in neuroimmune interaction due to CGRP in the TG via NF-κB signaling pathway.

Headache and immunological/autoimmune disorders: a comprehensive review of available epidemiological evidence with insights on potential underlying mechanisms

“…The upregulation of pro-inflammatory cytokines-specifically IL-1ß-in activated microglia has also been shown in the TNC. Using different models of trigeminal activation, the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-Κb) signalling pathway and activation of NLR family pyrin domain containing 3 (NLRP) inflammasome were found to play a role in neuron-glia cross-talk contributing to the central sensitization [17][18][19][20].…”

CGRP as a potential mediator for the sexually dimorphic responses to traumatic brain injury

“…CGRP is recognized as a critical player in migraine pathophysiology [ 66 ]. In the context of injured brains, however, it has been demonstrated to confer neuroprotective effects by diminishing oxidative stress [ 64 , 67 ], mitigating neuroinflammation [ 68 ], and modulating cerebral blood flow through vasodilation [ 69 ]. Prior investigations emphasize the significance of CGRP expression in correlation with female sex hormone concentrations in both normal and migraine-affected brains.…”

Src Family Kinases Facilitate the Crosstalk between CGRP and Cytokines in Sensitizing Trigeminal Ganglion via Transmitting CGRP Receptor/PKA Pathway

“…Interestingly, SFKs-mediated CCL2 gene expression and histone H3 acetylation at the CCL2 promoter are associated in macrophages [ 76 ]. Furthermore, CGRP is a potent neuroinflammatory mediator that induces the expression and release of cytokines in the TG [ 11 , 12 , 13 , 14 ], including IL-1β, CCL2, CXCL1, all of which in turn stimulate CGRP release [ 16 , 77 ], thereby inducing a positive feedback loop of TG sensitization. Similar to CGRP, IL-1β can activate SFKs in several cell lines [ 78 , 79 , 80 , 81 ], which suggests that released cytokines are highly likely to strengthen SFKs activity again to induce CGRP release and aggravate TG sensitization.…”

“…Active signaling mediated mainly by neuropeptides and inflammatory mediators occurs within the TG, among which calcitonin gene-related peptide (CGRP), the key drug target of migraine prevention and therapy, is a key player [ 8 ]. In the TG, released CGRP binds to CGRP receptor to facilitate neuronal excitability [ 9 , 10 , 11 ] and neuroinflammation, including elevated release and expression of inflammatory cytokines [ 11 , 12 , 13 , 14 ]. Importantly, cytokines can signal back to neurons, which promotes CGRP synthesis and release [ 15 , 16 ], thereby inducing a positive feedback loop of sensitization.…”