TNFα Levels and Macrophages Expression Reflect an Inflammatory Potential of Trigeminal Ganglia in a Mouse Model of Familial Hemiplegic Migraine

Abstract

Latent changes in trigeminal ganglion structure and function resembling inflammatory conditions may predispose to acute attacks of migraine pain. Here, we investigated whether, in trigeminal sensory ganglia, cytokines such as TNFα might contribute to a local inflammatory phenotype of a transgenic knock-in (KI) mouse model of familial hemiplegic migraine type-1 (FHM-1). To this end, macrophage occurrence and cytokine expression in trigeminal ganglia were compared between wild type (WT) and R192Q mutant CaV2.1 Ca2+ channel (R192Q KI) mice, a genetic model of FHM-1. Cellular and molecular characterization was performed using a combination of confocal immunohistochemistry and cytokine assays. With respect to WT, R192Q KI trigeminal ganglia were enriched in activated macrophages as suggested by their morphology and immunoreactivity to the markers Iba1, CD11b, and ED1. R192Q KI trigeminal ganglia constitutively expressed higher mRNA levels of IL1β, IL6, IL10 and TNFα cytokines and the MCP-1 chemokine. Consistent with the report that TNFα is a major factor to sensitize trigeminal ganglia, we observed that, following an inflammatory reaction evoked by LPS injection, TNFα expression and macrophage occurrence were significantly higher in R192Q KI ganglia with respect to WT ganglia. Our data suggest that, in KI trigeminal ganglia, the complex cellular and molecular environment could support a new tissue phenotype compatible with a neuroinflammatory profile. We propose that, in FHM patients, this condition might contribute to trigeminal pain pathophysiology through release of soluble mediators, including TNFα, that may modulate the crosstalk between sensory neurons and resident glia, underlying the process of neuronal sensitisation.

Sex and the migraine brain

“…(2) Cytokines . Several lines of evidence support cytokines role in migraine: (a) migraine patients have higher serum IL-1beta and IL-6 levels, and lower IL-10 levels than healthy subjects (158); (b) the trigeminal ganglia of a transgenic mouse model of familial hemiplegic migraine contains high level of TNF-α, IL-1β, IL-6, and IL-10 (159); (c) menstruation is an inflammatory process (160); and (d) increased levels of peripheral and central cytokines can alter neuronal activity in the central nervous system (161) (162, 163). (3) Microglia.…”

“…Inflammation has been a consistent theme in migraine in humans (183-185) and animal models (159). We suggest that there are a number of important routes of research that may help us better understand how hormones affect the migraine brain.…”

Traumatic Brain Injury, Neuroinflammation, and Post‐Traumatic Headaches

“…123 For example, calcitonin gene-related peptide released from trigeminal nerve cell bodies has been shown to stimulate SGCs to release inflammatory substances, 67 which in turn can influence neuronal function and excitability through processes including upregulation of receptors for the inflammatory mediators and lowered activation thresholds 107 in a feed-forward loop. 124,125 This neuronal-glial signaling is suspected to play a role in sensitizing afferent trigeminal nociceptors, 122,126,127 potentially leading to sensitization of second-order neurons 101,128 and mediating central pain sensitization. 67,129 Prolonged inflammation and chronic hyperexcitability are thought to predispose to a pathological pain state.…”

Cav2.1 Channels and Migraine

“…Moreover, a stronger basal activation of macrophages, a larger basal release of TNFa, and an enhanced P2X3 receptor-mediated neuronal current have been recently reported in cultured TG neurons from these mice (Franceschini et al 2013a;Nair et al 2010). Also intact trigeminal ganglia of R192Q knockin mice appear enriched in activated macrophages both in the absence and presence of a standard inflammatory stimulus (Franceschini et al 2013b). On the basis of these findings, it has been suggested that FHM1 mutations might lead to a basal inflammatory milieu within the trigeminal ganglion (Franceschini et al 2013a) (but of similar levels of inflammatory cytokines in TG extracts from WT and R192Q knockin mice in (Franceschini et al 2013b)).…”

“…Also intact trigeminal ganglia of R192Q knockin mice appear enriched in activated macrophages both in the absence and presence of a standard inflammatory stimulus (Franceschini et al 2013b). On the basis of these findings, it has been suggested that FHM1 mutations might lead to a basal inflammatory milieu within the trigeminal ganglion (Franceschini et al 2013a) (but of similar levels of inflammatory cytokines in TG extracts from WT and R192Q knockin mice in (Franceschini et al 2013b)). Interestingly, in both cultured TG neurons and intact ganglia a larger fraction of TG neurons was immunoreactive for active phosphorylated CaMKII in R192Q knockin compared to WT mice.…”