Involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in Experimental Models of Migraine

Abstract

Background The exact molecular mechanisms of migraine were not fully understood. Emerging evidence indicated that inflammation had a significant role in pathophysiological mechanisms of migraine. The present study aimed to investigate the role of Interleukin-18-Mediated Microglia/Astrocyte Interaction in the development of hyperpathia or allodynia induced by migraine. Methods Experimental rat model of migraine was established by repetitive inflammatory soup (IS) dural infusions. The expression of Interleukin-18 (IL-18) and IL-18 receptor (IL-18R) was examined by quantitative real-time polymerase chain reaction or Western blot. The expression of activated microglia and astrocytes was examined by Western blot or immunofluorescence. The expression of nuclear factor-kappa B (NF-κB) was examined by Western blot. TAK-242 and anti-IL-18 antibody were used to inhibit the activation of toll-like receptor 4 (TLR4) and IL-18 pathway, respectively. Results IS dural infusions elicited microglial activation and astrocytic activation. Meanwhile, IS dural infusions induced the upregulation of IL-18 and IL-18R in microglia and astrocytes, respectively. Blocking the IL-18 signaling pathway attenuated nociceptive behavior. Meanwhile, blocking IL-18 signaling also suppressed astrocytic activation, as well as activation of NF-κB. And IL-18 dural infusions induced nociceptive behavior and glia activation. Conclusions IL-18, a product of microglial toll-like receptor 4 (TLR4) activation, acted on IL-18R expressed in astrocyte, and subsequently stimulated activation of NF-κB, leading to the astrocytic activation. Together, the present results suggest that IL-18-mediated microglia/astrocyte interactions in the medullary dorsal horn may participate in the development of hyperpathia or allodynia induced by migraine.