Red nucleus IL-33 facilitates the early development of mononeuropathic pain in male rats by inducing TNF-\u03b1 through activating ERK, p38 MAPK, and JAK2/STAT3

Hao-Nan Li,Qing-Qing Yang,Yuan-Wu Zou,Xue Tian,Wen-Tao Wang,Jun-Yang Wang,Fan Feng,Jia-Xue Wang,Xiao-Yan Zeng,Shu-Ting Zhang,Yu-Tong Xia

doi:10.1186/s12974-021-02198-9

Abstract

BackgroundOur recent studies have identified that the red nucleus (RN) dual-directionally modulates the development and maintenance of mononeuropathic pain through secreting proinflammatory and anti-inflammatory cytokines. Here, we further explored the action of red nucleus IL-33 in the early development of mononeuropathic pain.MethodsIn this study, male rats with spared nerve injury (SNI) were used as mononeuropathic pain model. Immunohistochemistry, Western blotting, and behavioral testing were used to assess the expressions, cellular distributions, and actions of red nucleus IL-33 and its related downstream signaling molecules.ResultsIL-33 and its receptor ST2 were constitutively expressed in the RN in naive rats. After SNI, both IL-33 and ST2 were upregulated significantly at 3 days and peaked at 1 week post-injury, especially in RN neurons, oligodendrocytes, and microglia. Blockade of red nucleus IL-33 with anti-IL-33 neutralizing antibody attenuated SNI-induced mononeuropathic pain, while intrarubral administration of exogenous IL-33 evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 generated an algesic effect in the early development of SNI-induced mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3, suppression of NF-κB, ERK, p38 MAPK, and JAK2/STAT3 with corresponding inhibitors markedly attenuated SNI-induced mononeuropathic pain or IL-33-evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 contributed to SNI-induced mononeuropathic pain by stimulating TNF-α expression, which could be abolished by administration of inhibitors against ERK, p38 MAPK, and JAK2/STAT3, but not NF-κB.ConclusionsThese results suggest that red nucleus IL-33 facilitates the early development of mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3. IL-33 mediates algesic effect partly by inducing TNF-α through activating ERK, p38 MAPK and JAK2/STAT3.

Highlights

Red nucleus (RN) is a prominent nucleus in extrapyramidal system, locating in the center of tegmental part of midbrain
Red nucleus IL-33 facilitates the early development of mononeuropathic pain by activating p38 mitogen-activated protein kinase (MAPK) signaling pathway We explored whether MAPK signaling pathways, including extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK), contribute to red nucleus IL-33-mediated algesic effect
Intrarubral pre-injection of PD98059 or SB203580, 30 min before IL-33 administration, significantly attenuated IL-33-evoked mechanical hypersensitivity, while intrarubral injection of PD98059 or SB203580 alone had no influence on the mechanical paw withdrawal threshold (PWT) of naive rats (Fig. 4E and Fig. 5E). These results demonstrate that red nucleus IL-33 facilitates the early development of mononeuropathic pain by activating ERK and p38 MAPK in MAPK signaling pathway rather than JNK

Summary

Introduction

Red nucleus (RN) is a prominent nucleus in extrapyramidal system, locating in the center of tegmental part of midbrain. It receives fiber projections mainly from cerebral cortex and cerebellum, and transmits to the spinal cord Rexed’s laminae V and VI as well as in the dorsal part of lamina VII through the rubrospinal tract [1]. Functional magnetic resonance imaging studies indicate that the RN can be activated by painful stimuli, and the activity of RN is more driven by the requirements for sensory processing than by motor coordination per se [7, 8]. We further explored the action of red nucleus IL-33 in the early development of mononeuropathic pain

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Discussion

Conclusion