Loss of SHP1 in Spinal Astrocytes Triggers T‐Lymphocyte Infiltration and Nociceptive Hypersensitivity
- 1Department of Translational Neuroscience Jing'an District Centre Hospital of Shanghai State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center For Brain Science Institutes of Brain Science Fudan University Shanghai China
- 2Department of Endocrinology Huadong Hospital; Key Laboratory of Computational Neuroscience and Brain‐Inspired Intelligence Ministry of Education; Behavioral and Cognitive Neuroscience Center Institute of Science and Technology for Brain‐Inspired Intelligence MOE Frontiers Center for Brain Science Fudan University Shanghai China
- 3Department of Pathology and Pathophysiology Shantou University Medical College Shantou China
Abstract
Chronic pain is sustained by complex neuroimmune interplay within the spinal cord, yet how astrocytes constrain immune amplification remains poorly understood. Here we identified Src‐homology 2 domain‐containing protein tyrosine phosphatase‐1 (SHP1; encoded by Ptpn6) as a key suppressor of spinal neuroinflammation and nociceptive hypersensitivity. Astrocyte‐specific SHP1 deletion in the spinal dorsal horn induced profound astrocytic morphological changes, increased C‐X‐C motif chemokine ligand 10 (CXCL10) expression, disrupted blood‐brain barrier (BBB) integrity, and facilitated the infiltration of activated T lymphocytes into the spinal parenchyma. These infiltrating T cells promoted microglial activation, enhanced excitatory synaptic transmission, increased the excitability of somatostatin (SOM)‐positive neurons, and ultimately triggered nociceptive hypersensitivity. Mechanistically, T cell recruitment was governed by an SHP1‐dependent regulatory circuit, in which SHP1‐mediated Signal transducer and activator of transcription 1 (STAT1) dephosphorylation restrained Cxcl10 transcription. Blocking the STAT1–CXCL10–CXCR3 signaling axis alleviated T cell infiltration and nociceptive hypersensitivity. Notably, we found that during the development of neuropathic pain, spinal SHP1 expression was significantly downregulated, accompanied by upregulation of CXCL10. Overexpression of SHP1 in astrocytes markedly attenuated astrocyte activation and alleviated mechanical allodynia induced by spared nerve injury (SNI). Collectively, our findings revealed an astrocyte‐defined immune checkpoint that restrains neuroinflammatory escalation and pain persistence, emphasizing SHP1 as a promising therapeutic target for chronic pain.
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BibTeX
@article{yi2026loss,
title = {{Loss of SHP1 in Spinal Astrocytes Triggers T‐Lymphocyte Infiltration and Nociceptive Hypersensitivity}},
author = {Lan‐Xing Yi and Lin Yang and Kang‐Li Wang and Hui‐Zhu Liu and Rui‐Ying Chen and Min Su and Xiao Xiao and Yu‐Qiu Zhang},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.76932},
url = {https://doi.org/10.1002/advs.76932},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Loss of SHP1 in Spinal Astrocytes Triggers T‐Lymphocyte Infiltration and Nociceptive Hypersensitivity
AU - Lan‐Xing Yi
AU - Lin Yang
AU - Kang‐Li Wang
AU - Hui‐Zhu Liu
AU - Rui‐Ying Chen
AU - Min Su
AU - Xiao Xiao
AU - Yu‐Qiu Zhang
PY - 2026
DA - 2026/08/03
JO - Advanced Science
DO - 10.1002/advs.76932
UR - https://doi.org/10.1002/advs.76932
AB - Chronic pain is sustained by complex neuroimmune interplay within the spinal cord, yet how astrocytes constrain immune amplification remains poorly understood. Here we identified Src‐homology 2 domain‐containing protein tyrosine phosphatase‐1 (SHP1; encoded by Ptpn6) as a key suppressor of spinal neuroinflammation and nociceptive hypersensitivity. Astrocyte‐specific SHP1 deletion in the spinal dorsal horn induced profound astrocytic morphological changes, increased C‐X‐C motif chemokine ligand 10 (CXCL10) expression, disrupted blood‐brain barrier (BBB) integrity, and facilitated the infiltration of activated T lymphocytes into the spinal parenchyma. These infiltrating T cells promoted microglial activation, enhanced excitatory synaptic transmission, increased the excitability of somatostatin (SOM)‐positive neurons, and ultimately triggered nociceptive hypersensitivity. Mechanistically, T cell recruitment was governed by an SHP1‐dependent regulatory circuit, in which SHP1‐mediated Signal transducer and activator of transcription 1 (STAT1) dephosphorylation restrained Cxcl10 transcription. Blocking the STAT1–CXCL10–CXCR3 signaling axis alleviated T cell infiltration and nociceptive hypersensitivity. Notably, we found that during the development of neuropathic pain, spinal SHP1 expression was significantly downregulated, accompanied by upregulation of CXCL10. Overexpression of SHP1 in astrocytes markedly attenuated astrocyte activation and alleviated mechanical allodynia induced by spared nerve injury (SNI). Collectively, our findings revealed an astrocyte‐defined immune checkpoint that restrains neuroinflammatory escalation and pain persistence, emphasizing SHP1 as a promising therapeutic target for chronic pain.
SN - 2198-3844
ER -