Background & Aims
T cells have emerged as sex-dependent orchestrators of pain chronification but the sexually dimorphic mechanisms by which T cells control pain sensitivity is still unresolved. Here, we describe pain governance by regulatory T cells (Treg) that is distinct from their canonical functions of immune regulation and tissue repair. To assess the role of meningeal Tregs in gating pain sensitivity we specifically depleted Tregs in the meningeal compartment.
Methods
Mechanical hypersensitivity was measured in mice of both sexes at steady-state and after a spared nerve injury (SNI) model of neuropathic pain. Meningeal Tregs were depleted using intrathecal injections of pegylated diphtheria toxin in FoxP3-DTR mice. Alternatively, meningeal Tregs were expanded using intrathecal injections of low dose IL-2. Penk KO:FoxP3-DTR mixed bone marrow chimeras were generated to assess the role of meningeal Treg-derived enkephalins. The requirement of the delta opioid receptor (DOR) in Treg-mediated analgesia was assessed using a pharmacological tools as well as in DOR fl/fl mice. 30 days post-nerve injury, female mice were mated and tested to assess the role of meningeal Tregs in the mediation of pregnancy-induced analgesia.
Results
Meningeal Tregs (mTregs) were necessary and sufficient for suppressing mechanical pain sensitivity in female but not male mice. mTregs expressed higher levels of the endogenous opioid, enkephalin, and mTreg-derived enkephalin was required for anti-nociception through presynaptic opiate receptor signaling but was dispensable for immunosuppression. Notably, mTreg-derived modulation of pain thresholds depended on sex-hormones and expansion of enkephalinergic mTreg during gestation imparted a remarkable pregnancy-induced analgesia to pre-existing, chronic, neuropathic pain.
Conclusions
These results uncover a fundamental sex-specific and pregnancy-pronounced immunological endogenous opioid circuit of nociceptive regulation with critical implications for pain biology and maternal health.
References
Julia A Kuhn, Ilia D Vainchtein, Joao Braz, Katherine Hamel, Mollie Bernstein, Veronica Craik, Madelene W Dahlgren, Jorge Ortiz-Carpena, Ari B Molofsky, Anna V Molofsky, Allan I Basbaum. Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice. Elife. 2021 Oct 15:10:e69056. doi: 10.7554/eLife.69056.
Sarah F Rosen, Boram Ham, Shannon Drouin, Nadia Boachie, Anne-Julie Chabot-Dore, Jean-Sebastien Austin, Luda Diatchenko, Jeffrey S Mogil. T-Cell Mediation of Pregnancy Analgesia Affecting Chronic Pain in Mice. J Neurosci. 2017 Oct 11;37(41):9819-9827. doi: 10.1523/JNEUROSCI.2053-17.2017. Epub 2017 Sep 6.
Presenting Author
Élora Midavaine
Poster Authors
Topics
- Gender/Sex Differences