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

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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-IL­17A 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.

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Acknowledgments

The authors thank the Prof. Xiang Cheng from the Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology for assistance with knockout mice-related lab work.

Conflict of Interest

The authors declare that they have no competing interest.

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    Authors and Affiliations

    1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

      Cheng-ye Yao

    2. Department of Pain, The Second Hospital of Xiamen, Xiamen, People’s Republic of China

      Ze-lin Weng

    3. Department of Anesthesia, Institute of Anesthesia and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China

      Jian-cheng Zhang, Tao Feng, Yun Lin & Shanglong Yao

    4. Department of Critical Care Medicine, Institute of Anesthesia and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

      Jian-cheng Zhang, Yun Lin & Shanglong Yao

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    Correspondence to Yun Lin.

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    Cheng-ye Yao, Ze-lin Weng and Jian-cheng Zhang contributed equally to this work.

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    Yao, Cy., Weng, Zl., Zhang, Jc. et al. Interleukin-17A Acts to Maintain Neuropathic Pain Through Activation of CaMKII/CREB Signaling in Spinal Neurons. Mol Neurobiol 53, 3914–3926 (2016). https://doi.org/10.1007/s12035-015-9322-z

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    • DOI: https://doi.org/10.1007/s12035-015-9322-z

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