Traumatic Brain Injury Stimulates Sympathetic Tone-mediated Bone Marrow Myelopoiesis to Favor Fracture Healing

Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system plays a pivotal role in regulating immune system and skeleton, however, the impact of TBI on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. Importantly, the adrenergic hypersensitivity swiftly skews bone marrow hematopoietic lineage cells toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of ß3- or ß2-adrenergic receptors (ARs) eliminate TBI mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. Moreover, ß3- and ß2-ARs agonists synergistically promote M2 macrophages infiltration in callus and accelerate bone healing process. Our results suggest that TBI shapes the anti-inflammation environment during early stage of fracture healing, implicating the sympathetic nerve system as a potential target that can be exploited to treat fracture. Overall design: Comparative gene expression profiling analysis of RNA-seq data of the bone marrow cells from wild type mice, Adrb2 knockout mice, and Adrb3 knockout mice after TBI and fracture.

创伤性脑损伤（Traumatic brain injury, TBI）可加速骨折愈合，但其潜在分子机制仍未明确。越来越多的研究证据表明，中枢神经系统在调控免疫系统与骨骼系统中发挥关键作用，但TBI对造血谱系定向分化的影响却长期被忽视。本研究发现，伴随TBI出现的交感紧张性显著升高可促进骨折愈合；化学性交感神经切除术可阻断TBI诱导的骨折愈合进程。值得注意的是，肾上腺素能高敏感性会在14天内快速促使骨髓造血谱系细胞向抗炎性髓系细胞极化，这一变化有利于骨折愈合。敲除β2或β3肾上腺素能受体（adrenergic receptors, ARs）可消除TBI介导的抗炎性巨噬细胞扩增以及TBI加速的骨折愈合。此外，β2和β3肾上腺素能受体激动剂可协同促进骨痂内M2型巨噬细胞浸润，进而加快骨愈合进程。本研究结果提示，TBI可在骨折愈合早期塑造抗炎微环境，表明交感神经系统可作为治疗骨折的潜在靶点。整体实验设计：对创伤性脑损伤合并骨折后的野生型小鼠、Adrb2基因敲除小鼠及Adrb3基因敲除小鼠的骨髓细胞进行RNA测序（RNA-seq）转录组比较分析。