Interleukin-17A Acts to Maintain Neuropathic Pain Through Activation of CaMKII/CREB Signaling in Spinal Neurons

Abstract

Immunity and neuroinflammation play major roles in neuropathic pain. Spinal interleukin (IL)-17A, as a mediator connecting innate and adaptive immunity, has been shown to be an important cytokine in neuroinflammation and acute neuropathic pain. However, the effects and underlying mechanisms of spinal IL-17A in the maintenance of neuropathic pain remain unknown. This study was designed to investigate whether spinal IL-17A acted to maintain neuropathic pain and to elucidate the underlying mechanisms in IL-17A knockout or wild-type (WT) mice following L4 spinal nerve ligation (L4 SNL). WT mice were treated with anti-IL-17A neutralized monoclonal antibody (mAb) or recombinant IL-17A (rIL-17A). We showed that IL-17A levels were significantly increased 1, 3, 7, and 14 days after SNL in spinal cord. Double immunofluorescence staining showed that astrocytes were the major cellular source of spinal IL-17A. IL-17A knockout or anti-IL-17A mAb treatment significantly ameliorated hyperalgesia 7 days after SNL, which was associated with a significant reduction of p-CaMKII and p-CREB levels in spinal cord, whereas rIL-17A treatment conferred the opposite effects. Furthermore, we showed that blocking CaMKII with KN93 significantly reduced SNL- or rIL-17A-induced hyperalgesia and p-CREB expression. Our in vitro data showed that KN93 also significantly inhibited rIL-17A-induced CREB activation in primary cultured spinal neurons. Taken together, our study indicates that astrocytic IL-17A plays important roles in the maintenance of neuropathic pain through CaMKII/CREB signaling pathway in spinal cord, and thus targeting IL-17A may offer an attractive strategy for the treatment of chronic persistent neuropathic pain.

Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain

“…This study examined the CaMKII/CREB pathway because it is important for the modulation of spinal central sensitization in chronic pain. Accumulating evidence suggests that CaMKII/CREB is functionally implicated in animal models of inflammatory pain 42 , neuropathic pain 43 and visceral pain 44 . Therefore, we herein investigated whether CaMKII/CREB was stimulated in the bone cancer state and contributed to pain sensitization.…”

Neuropathic Pain: Central vs. Peripheral Mechanisms

“…Resident astrocytes, as well as CD4 + T cells infiltrating the dorsal horn, secrete IL-17 following SNL. The resultant expression of IL-1β and IL-6 is, along with TNF-α, important in the maintenance of neuropathic pain [87][88][89]. ATP is released by injured dorsal horn neurons [90], whereupon microglial purinergic receptors are activated, leading to microglial proliferation and neuropathic pain [91-94, 95•].…”

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

“…The use of humanised monoclonal antibodies (mAbs) to fight disease has a strong precedent, including therapy for inflammatory [176] and neuropathic pain [177,178]. All mAbs are high-molecular-weight immunoglobulins (typically of the IgG class) with two heavy and two light chains with variable domains that bind to antigens and Fc constant domains with effector functions.…”