Critical role of microglial CD40 in the maintenance of mechanical hypersensitivity in a murine model of neuropathic pain

Abstract

We recently demonstrated a contributing role of spinal cord infiltrating CD4⁺ T lymphocytes in the maintenance of mechanical hypersensitivity in a rodent model of neuropathic pain, spinal nerve L5 transection (L5Tx). It has been demonstrated that microglia play a role in the etiology of pain states. We hypothesized that infiltrating CD4⁺ T lymphocytes communicate with microglia via a CD40‐CD154 interaction. Here, we investigated the role of CD40 in the development of mechanical hypersensitivity post‐L5Tx. CD40 KO mice displayed significantly decreased mechanical sensitivity compared with WT mice starting from day 5 post‐L5Tx. Using bone marrow chimeric mice, we further identified a pro‐nociceptive role of CNS microglial CD40 rather than the peripheral leukocytic CD40. Flow cytometric analysis determined a significant increase of CD40⁺ microglia in the ipsilateral side of lumbar spinal cord post‐L5Tx. Further, spinal cord proinflammatory cytokine (IL‐1β, IL‐6, IL‐12, and TNF‐α) profiling demonstrated an induction of IL‐6 in both WT and CD40 KO mice post‐L5Tx prior to the increase of microglial CD40 expression, indicating a CD40‐independent induction of IL‐6 following L5Tx. These data establish a novel role of microglial CD40 in the maintenance of nerve injury‐induced behavioral hypersensitivity, a behavioral sign of neuropathic pain.