Differential Effects of Regulatory T Cells in the Meninges and Spinal Cord of Male and Female Mice with Neuropathic Pain

Abstract

Immune cells play a critical role in promoting neuroinflammation and the development of neuropathic pain. However, some subsets of immune cells are essential for pain resolution. Among them are regulatory T cells (Tregs), a specialised subpopulation of T cells that limit excessive immune responses and preserve immune homeostasis. In this study, we utilised intrathecal adoptive transfer of activated Tregs in male and female mice after peripheral nerve injury to investigate Treg migration and whether Treg-mediated suppression of pain behaviours is associated with changes in peripheral immune cell populations in lymphoid and meningeal tissues and spinal microglial and astrocyte reactivity and phenotypes. Treatment with Tregs suppressed mechanical pain hypersensitivity and improved changes in exploratory behaviours after chronic constriction injury (CCI) of the sciatic nerve in both male and female mice. The injected Treg cells were detected in the choroid plexus and the pia mater and in peripheral lymphoid organs in both male and female recipient mice. Nonetheless, Treg treatment resulted in differential changes in meningeal and lymph node immune cell profiles in male and female mice. Moreover, in male mice, adoptive transfer of Tregs ameliorated the CCI-induced increase in microglia reactivity and inflammatory phenotypic shift, increasing M2-like phenotypic markers and attenuating astrocyte reactivity and neurotoxic astrocytes. Contrastingly, in CCI female mice, Treg injection increased astrocyte reactivity and neuroprotective astrocytes. These findings show that the adoptive transfer of Tregs modulates meningeal and peripheral immunity, as well as spinal glial populations, and alleviates neuropathic pain, potentially through different mechanisms in males and females.

Glucose competition between endothelial cells in the blood-spinal cord barrier and infiltrating regulatory T cells is linked to sleep restriction-induced hyperalgesia

“…Controversially, Tregs can either inhibit the inflammation [ 44 ], or stimulate the progression of bone cancer pain (unpublished data in our research group). Nathan et al [ 45 ] reported different changes in meningeal and lymph node immune cell profiles between male and female mice. Inflammation is a process influenced by metabolism [ 46 , 47 ], and we therefore speculated that the different functions of Tregs may be attributed to the metabolic mode.…”

Involvement of interferon gamma signaling in spinal trigeminal caudal subnucleus astrocyte in orofacial neuropathic pain in rats with infraorbital nerve injury

“…60,61 It is well known that microglia are closely involved in neuropathic pain in male mice, whereas the neuropathic pain in female mice does not require microglia, but adaptive immune cells such as T lymphocytes to produce the same pain. [62][63][64] On the other hand, in studies of pain in female animals, it is necessary to keep the sex cycle of all female animals constant because estrogen is often involved. 65,66 In addition, there have been several studies that have examined the relationship between IFN-γ and pain, and it is necessary to compare the results of these studies with those of this study, but all of these studies used male rats.…”

Impact of inflammation and Treg cell regulation on neuropathic pain in spinal cord injury: mechanisms and therapeutic prospects

“…Treg treatment also modulates the amount of reactive astrocytes of different phenotypes to reduce neurotoxicity by attenuating astrocyte GFAP expression. Interestingly this therapeutic effect of Treg cells manifests itself differently in female and male mice, with a reduction in the number of neurotoxic astrocytes in peripherally injured male mice, and conversely, in peripherally injured females, the number of protective astrocytes was increased with peripheral nerve injury ( 135 ). Brain Treg cells inhibit neurotoxic astrocyte proliferation and protect neurons from damage by producing the low-affinity EGFR ligand AREG ( 136 ).…”