Critical role of microglial CD40 in the maintenance of mechanical hypersensitivity in a murine model of neuropathic pain.
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-1beta, IL-6, IL-12, and TNF-alpha) 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.
Cao
Ling
L
Department of Anesthesiology, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756, USA. lcao@UNE.edu
Palmer
Christopher D
CD
Malon
Jennifer T
JT
De Leo
Joyce A
JA
D000818:Animals; D016026:Bone Marrow Transplantation; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008159:Lumbar Vertebrae; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D010149:Postoperative Pain / Q000378:metabolism / Q000503:physiopathology*; D013116:Spinal Cord / Q000378:metabolism; D013127:Spinal Nerves / Q000601:surgery; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019013:CD40 Antigens; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha