Details

Autor(en) / Beteiligte

• Szabo-Pardi, Thomas A.
• Barron, Luz R.
• Lenert, Melissa E.
• Burton, Michael D.

Titel

Sensory Neuron TLR4 mediates the development of nerve-injury induced mechanical hypersensitivity in female mice

Ist Teil von

• Brain, behavior, and immunity, 2021-10, Vol.97, p.42-60

Ort / Verlag

Netherlands: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• •TLR4 on sensory neurons drive the early development of neuropathic pain in females.•ATF3 in Nav1.8 neurons is higher in females early after neuropathic injury.•Neuronal HMGB1 activation is mediated by TLR4 expression in females after injury.•TLR4 does not contribute to the development of cold allodynia after injury. Recent studies have brought to light the necessity to discern sex-specific differences in various pain states and different cell-types that mediate these differences. These studies have uncovered the role of neuroimmune interactions to mediate pain states in a sex-specific fashion. While investigating immune function in pain development, we discovered that females utilize immune components of sensory neurons to mediate neuropathic pain development. We utilized two novel transgenic mouse models that eitherrestore expression of toll-like receptor (TLR) 4 inNav1.8 nociceptors on a TLR4-null background (TLR4LoxTB) or remove TLR4 specifically from Nav1.8 nociceptors (TLR4fl/fl). After spared nerve injury (SNI), a model of neuropathic injury, we observed a robust female-specific onset of mechanical hypersensitivity in our transgenic animals. Female Nav1.8-TLR4fl/fl knockout animals were less mechanically sensitive than cre-negative TLR4fl/fl littermates. Conversely, female Nav1.8-TLR4LoxTB reactivated animals were as mechanically sensitive as their wild-type counterparts. These sex and cell-specific effects were not recapitulated in male animals of either strain. Additionally, we find the danger associated molecular pattern, high mobility group box-1 (HGMB1), a potent TLR4 agonist, localization and ATF3 expression in females is dependent on TLR4 expression in dorsal root ganglia (DRG) populations following SNI. These experiments provide novel evidence toward sensory neuron specific modulation of pain in a sex-dependent manner.