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.