Central microglia–adenosine-related signaling impairs bone–tendon interface repair via sympathetic ADRB2 activation
- 1Department of Sports Medicine, Xiangya Hospital Central South University
- 2Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province
Abstract
Bone–tendon interface (BTI) injuries pose a major clinical challenge because surgical repair often fails to restore the native enthesis and its structural and mechanical integrity. Although local repair mechanisms have been extensively studied, whether central neuroimmune circuits contribute to BTI healing remains unclear. Here, using a murine rotator cuff injury model, we provide evidence that BTI injury engages a sensory–central–sympathetic regulatory axis that contributes to impaired repair. BTI injury activated sensory afferent signaling and was associated with microglia-mediated neuroinflammation in the hypothalamic paraventricular nucleus (PVN), reduced PVN neuronal activity, and increased central adenosine-related signaling. Chemogenetic activation of PVN microglia suppressed PVN neuronal activity, enhanced sympathetic-associated changes, and impaired BTI healing, whereas microglial inhibition produced the opposite effects. Metabolomic, microdialysis, and pharmacological analyses identified extracellular adenosine as a microglia-associated signaling mediator, likely involving A1R-expressing PVN neurons. Downstream, increased sympathetic signaling at the healing interface was associated with elevated β2-adrenergic receptor (ADRB2) activity and reduced osteogenic and chondrogenic factor expression. Local ADRB2 blockade improved molecular, structural, and histological indices of BTI repair, supporting ADRB2 as a peripheral effector node of this neuroimmune–sympathetic pathway. Together, these findings suggest that central microglia–adenosine-related signaling contributes to BTI repair impairment through sympathetic ADRB2 activation. Targeting central neuroimmune signaling or local ADRB2 activity may provide potential strategies for improving BTI healing.
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BibTeX
@article{huang2026central,
title = {{Central microglia–adenosine-related signaling impairs bone–tendon interface repair via sympathetic ADRB2 activation}},
author = {Tingmo Huang and Liyang Wan and Ruixue Du and Liyue Zeng and Wenjie Li and Feifei Yuan and Hongbin Lu},
journal = {Journal of Neuroinflammation},
year = {2026},
month = jul,
doi = {10.1186/s12974-026-03977-y},
url = {https://doi.org/10.1186/s12974-026-03977-y},
note = {CC BY},
}
RIS
TY - JOUR
TI - Central microglia–adenosine-related signaling impairs bone–tendon interface repair via sympathetic ADRB2 activation
AU - Tingmo Huang
AU - Liyang Wan
AU - Ruixue Du
AU - Liyue Zeng
AU - Wenjie Li
AU - Feifei Yuan
AU - Hongbin Lu
PY - 2026
DA - 2026/07/01
JO - Journal of Neuroinflammation
DO - 10.1186/s12974-026-03977-y
UR - https://doi.org/10.1186/s12974-026-03977-y
AB - Bone–tendon interface (BTI) injuries pose a major clinical challenge because surgical repair often fails to restore the native enthesis and its structural and mechanical integrity. Although local repair mechanisms have been extensively studied, whether central neuroimmune circuits contribute to BTI healing remains unclear. Here, using a murine rotator cuff injury model, we provide evidence that BTI injury engages a sensory–central–sympathetic regulatory axis that contributes to impaired repair. BTI injury activated sensory afferent signaling and was associated with microglia-mediated neuroinflammation in the hypothalamic paraventricular nucleus (PVN), reduced PVN neuronal activity, and increased central adenosine-related signaling. Chemogenetic activation of PVN microglia suppressed PVN neuronal activity, enhanced sympathetic-associated changes, and impaired BTI healing, whereas microglial inhibition produced the opposite effects. Metabolomic, microdialysis, and pharmacological analyses identified extracellular adenosine as a microglia-associated signaling mediator, likely involving A1R-expressing PVN neurons. Downstream, increased sympathetic signaling at the healing interface was associated with elevated β2-adrenergic receptor (ADRB2) activity and reduced osteogenic and chondrogenic factor expression. Local ADRB2 blockade improved molecular, structural, and histological indices of BTI repair, supporting ADRB2 as a peripheral effector node of this neuroimmune–sympathetic pathway. Together, these findings suggest that central microglia–adenosine-related signaling contributes to BTI repair impairment through sympathetic ADRB2 activation. Targeting central neuroimmune signaling or local ADRB2 activity may provide potential strategies for improving BTI healing.
SN - 1742-2094
ER -