TY - JOUR
T1 - Red nucleus IL-33 facilitates the early development of mononeuropathic pain in male rats by inducing TNF-α through activating ERK, p38 MAPK, and JAK2/STAT3
AU - Li, Hao Nan
AU - Yang, Qing Qing
AU - Wang, Wen Tao
AU - Tian, Xue
AU - Feng, Fan
AU - Zhang, Shu Ting
AU - Xia, Yu Tong
AU - Wang, Jia Xue
AU - Zou, Yuan Wu
AU - Wang, Jun Yang
AU - Zeng, Xiao Yan
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (No. 31640032) and Natural Science Foundation of Shaanxi Province, China (No. 2016JM3028, 2021JZ-06).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Background: Our 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. Methods: In 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. Results: IL-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. Conclusions: These 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.
AB - Background: Our 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. Methods: In 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. Results: IL-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. Conclusions: These 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.
KW - Interleukin-33
KW - Mononeuropathic pain
KW - Red nucleus
KW - Signaling pathway
KW - Tumor necrosis factor-α
UR - http://www.scopus.com/inward/record.url?scp=85109708112&partnerID=8YFLogxK
U2 - 10.1186/s12974-021-02198-9
DO - 10.1186/s12974-021-02198-9
M3 - Article
C2 - 34225736
AN - SCOPUS:85109708112
SN - 1742-2094
VL - 18
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
IS - 1
M1 - 150
ER -