Spinal microglia-derived TNF promotes the astrocytic JNK/CXCL1 pathway activation in a mouse model of burn pain.

Abstract

Burn injury-induced pain (BIP) is an extremely complicated condition usually resistant to analgesic drugs, while its pathogenesis remains unknown. Considerable attention has been attracted to elucidate the glial mechanisms in chronic pain. In this study, we initiatively used a mouse model of second-degree BIP to investigate the underlying non-neuronal mechanisms at the spinal cord level. Our behavioral results showed that hind-paw burn injury caused persistent allodynia and hyperalgesia for 2 weeks in mice. Further studies revealed that both microglia and astrocytes activated in a spatially- and temporally-dependent manner in spinal cord after burn injury. In addition, the phosphorylated p38 mitogen-activated protein kinase (MAPK)-mediated tumor necrosis factor (TNF) release in spinal microglia is essentially attributed to the early stage of BIP, while the c-Jun N-terminal kinase (JNK) MAPK-dependent chemokine CXCL1 expression is mainly involved in the maintenance of pain hypersensitivity. Most strikingly, burn injury-induced pain symptoms and the activation of astrocytes were significantly suppressed by TNF inhibitor Thalidomide. On the contrary, intrathecal injection of TNF caused apparent pain hypersensitivity, accompanied by the activation of astrocytes and the upregulation of CXCL1 via the JNK MAPK signaling pathway, indicating that TNF is the key cytokine in the interaction between microglia and astrocytes at the spinal level. Moreover, treatment with the CXCR2 receptor antagonist SB225002 to block the biological activities of CXCL1 significantly attenuated the mechanical allodynia and thermal hyperalgesia in this BIP model. Taken together, this study indicates that intervention of glial pathways provides a new perspective in the management of BIP.

• Authors: Run Zhang, Biao Xu, Nan Zhang, Jiandong Niu, Mengna Zhang, Qinqin Zhang, Dan Chen, Yonghang Shi, Danni Chen, Kedi Liu, Xiaodi Zhang, Ning Li, Quan Fang
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 102 Pg. 23-39 (05 2022) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 35143878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Chemokine CXCL1
• Cxcl1 protein, mouse
• Tumor Necrosis Factor-alpha
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Astrocytes (metabolism)
• Burns (metabolism, pathology)
• Chemokine CXCL1 (metabolism, pharmacology)
• Disease Models, Animal
• Hyperalgesia (metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• MAP Kinase Signaling System
• Mice
• Microglia (metabolism)
• Pain (etiology, metabolism, pathology)
• Spinal Cord (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)