Inhibition of Janus kinase/signal transducer and activator of transcription reduces nociceptive sensitization in a murine model of complex regional pain syndrome.

INTRODUCTION

Complex regional pain syndrome (CRPS) is a disabling condition relying in part on the production of pain-supporting autoantibodies. The Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling system regulates the adaptive system of immunity and is targeted to control autoimmune diseases.

OBJECTIVES

To evaluate the hypothesis that JAK-STAT inhibition could reduce the behavioral, cellular, and biochemical correlates of CRPS in a well-characterized murine tibia fracture model.

METHODS

Tofacitinib was used to inhibit JAK-STAT activity. Mechanical sensitization and hindlimb unweighting were used to follow nociceptive changes. Assays of regional lymph node hypertrophy, germinal center formation, and autoantibody production probed activation of adaptive immunity while single cell mass cytometry (CyTOF) identified specific cell sets sensitive to tofacitinib in this model.

RESULTS

Tofacitinib reduced hindlimb allodynia and unweighting in male and female mice after tibial fracture. Subsequent experiments focused on male mice showed reduced autoantibody binding to keratin 16, histone 3.2, GFAP, and NMDAR2B in fracture animals treated with tofacitinib. The enhanced deposition of IgM in the skin of fracture limb hind paws was also eliminated by tofacitinib. Correspondingly, tofacitinib reduced lymph node hypertrophy and germinal center formation. Mass cytometry demonstrated that CD4+ and CD8+ T lymphocytes in regional lymph nodes show tofacitinib-sensitive changes in the activation of key immune signaling systems after fracture including BCL6, IkB, pCREB, and pS6. Conversely, enhanced production of the innate immune mediators IL-1β and IL-6 were not suppressed by tofacitinib.

CONCLUSIONS

We conclude that tofacitinib reduces the regional nociceptive changes found in a murine model of CRPS possibly through inhibition of autoantibody production.