Spinal cord oligodendrocyte‐derived alarmin IL‐33 mediates neuropathic pain

ABSTRACT Neuropathic pain from injury to the peripheral and CNS represents a major health care issue. We have investigated the role of IL‐33/IL‐33 receptor (ST2) signaling in experimental models of neuropathic pain in mice. Chronic constriction injury (CCI) of the sciatic nerve induced IL‐33 production in the spinal cord. IL‐33/citrine reporter mice revealed that oligodendrocytes are the main cells expressing IL‐33 within the spinal cord together with a minor expression by neurons, microglia, and astrocytes. CCI‐induced mechanical hyperalgesia was reduced in IL‐33R (ST2)‐/‐ mice compared with wild‐type (WT) mice. Intrathecal treatment of WT mice with soluble IL‐33 receptor (IL‐33 decoy receptor) markedly reduced CCI‐induced hyperalgesia. Consistent with these observations, intrathecal injection of IL‐33 enhanced CCI hyperalgesia and induced hyperalgesia in naive mice. IL‐33‐mediated hyperalgesia during CCI was dependent on a reciprocal relationship with TNF‐α and IL‐1β. IL‐33‐induced hyperalgesia was markedly attenuated by inhibitors of PI3K, mammalian target of rapamycin, MAPKs (p38, ERK, and JNK), NF‐κB, and also by the inhibitors of glial cells (microglia and astrocytes). Furthermore, targeting these signaling pathways and cells inhibited IL‐33‐induced TNF‐α and IL‐1β production in the spinal cord. Our study, therefore, reveals an important role of oligodendrocyte‐derived IL‐33 in neuropathic pain.— Zarpelon, A. C., Rodrigues, F. C., Lopes, A. H., Souza, G. R., Carvalho, T. T., Pinto, L. G., Xu, D., Ferreira, S. H., Alves‐Filho, J. C., McInnes, I. B., Ryffel, B., Quesniaux, V. F. J., Reverchon, F., Mortaud, S., Menuet, A., Liew, F. Y., Cunha, F. Q., Cunha, T. M., Verri, Jr., W. A. Spinal cord oligodendrocyte‐derived alarmin IL‐33 mediates neuropathic pain. FASEB J. 30, 54‐65 (2016). www.fasebj.org