Background & Aims
Complex regional pain syndrome (CRPS) is a debilitating chronic pain disorder with no effective treatments. Increasingly, aberrant immune regulation has been recognized in the induction and maintenance of CRPS pathology. While the functions of antigen presenting cells, microglia, and B cells have been studied, less is known about the role of T cells in CRPS. More recently, resident memory T cells (Trm), which help define a local tissue environments response, have been implicated in several autoimmune diseases, including psoriasis, vitiligo and rheumatoid arthritis. We hypothesize that systemic T cell dysfunction in CRPS contributes to pathological Trm development leading to disease development and persistence. Targeting T cell dysfunction through repurposing FDA approved therapies immune modulating therapies may provide a novel treatment strategy for CRPS.
Methods
Mouse tibia fracture model (TFM) of CRPS was generated, and pain hypersensitivity was measured by von Frey, Hargreaves and dynamic weight bearing assays. Hind limb skin, lymph node, bone marrow, and PBMCs, and DRG were collected from TFM and control mice at different time points. After enzymatic digestion and generation of single cell suspensions, T cell populations were analyzed in each tissue at different time points by flow cytometry for phenotypic and residency markers. Drugs targeting T cell dysfunction were evaluated in fracture mice at 5 weeks post-fracture. Behavior studies as well as T cell activation with GFP reporter mice, cytokine production, and intracellular phosphorylation assays were performed to assess drug efficacy and functional T cell phenotyping.
Results
TFM mice demonstrate increased presence of Trm populations in the skin that are phenotypically unique compared to other tissues and Trm from control mice. These Trm demonstrate increased CD103+ populations. Signaling markers associated with Trm development were upregulated in pathological Trm, which were autoreactive measured by activation in GFP reporter mice. Systemic T cell dysfunction across other tissues was observed in TFM mice. Experiments evaluating the effect of pharmacological blockade of Trm development signaling and depletion on TFM development, as well as Trm effector function are ongoing.
Conclusions
Increases in autoreactive pathological skin Trm populations provide a novel avenue for therapeutic intervention, where blockade of signaling for Trm development or systemic T cell dysfunction could prove beneficial for attenuating pain in CRPS.
References
David Clark J, Tawfik VL, Tajerian M, Kingery WS. Autoinflammatory and autoimmune contributions to complex regional pain syndrome. Molecular Pain. 2018;14. doi:10.1177/174480691879912711
Park, Simone L., and Laura K. Mackay. “Decoding Tissue-Residency: Programming and Potential of Frontline Memory T Cells.” Cold Spring Harbor Perspectives in Biology 13, no. 10 (October 1, 2021): a037960. https://doi.org/10.1101/cshperspect.a037960.