Traumatic brain injury(TBI)accelerates fracture healing,but the underlying mechanism remains largely unknown.Accumulating evidence indicates that the central nervous system(CNS)plays a pivotal role in regulating immun...Traumatic brain injury(TBI)accelerates fracture healing,but the underlying mechanism remains largely unknown.Accumulating evidence indicates that the central nervous system(CNS)plays a pivotal role in regulating immune system and skeletal homeostasis.However,the impact of CNS injury on hematopoiesis commitment was overlooked.Here,we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing;chemical sympathectomy blocks TBIinduced fracture healing.TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells(HSCs)and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days,which favor fracture healing.Knockout ofβ3-orβ2-adrenergic receptor(AR)eliminate TBI-mediated anti-inflammation macrophage expansion and TBIaccelerated fracture healing.RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells.Importantly,flow cytometry confirmed that deletion ofβ2-AR inhibits M2 polarization of macrophages at 7th day and 14th day;and TBI-induced HSCs proliferation was impaired inβ3-AR knockout mice.Moreover,β3-andβ2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process.Thus,we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow.These results implicate that the adrenergic signals could serve as potential targets for fracture management.展开更多
基金This study was partly supported by the National Natural Science Foundation of China(91949203 to Zhang Y.Z.,82102627 to Lv X.)Key Project of Hebei Provincial Natural Fund(H2020206456)+1 种基金Hubei Provincial Natural Science Foundation of China(2021CFB095)Wuhan Knowledge Innovation Project 2022020801020468.
文摘Traumatic brain injury(TBI)accelerates fracture healing,but the underlying mechanism remains largely unknown.Accumulating evidence indicates that the central nervous system(CNS)plays a pivotal role in regulating immune system and skeletal homeostasis.However,the impact of CNS injury on hematopoiesis commitment was overlooked.Here,we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing;chemical sympathectomy blocks TBIinduced fracture healing.TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells(HSCs)and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days,which favor fracture healing.Knockout ofβ3-orβ2-adrenergic receptor(AR)eliminate TBI-mediated anti-inflammation macrophage expansion and TBIaccelerated fracture healing.RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells.Importantly,flow cytometry confirmed that deletion ofβ2-AR inhibits M2 polarization of macrophages at 7th day and 14th day;and TBI-induced HSCs proliferation was impaired inβ3-AR knockout mice.Moreover,β3-andβ2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process.Thus,we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow.These results implicate that the adrenergic signals could serve as potential targets for fracture management.
