Toll-like receptors(TLRs)play pivotal roles in inflammation and provide important links between the immune and skeletal systems.Although the activation of TLRs may affect osteoclast differentiation and bone metabolism...Toll-like receptors(TLRs)play pivotal roles in inflammation and provide important links between the immune and skeletal systems.Although the activation of TLRs may affect osteoclast differentiation and bone metabolism,whether and how TLRs are required for normal bone remodeling remains to be fully explored.In the current study,we show for the first time that TLR9^(-/-)mice exhibit a low bone mass and low-grade systemic chronic inflammation,which is characterized by the expansion of CD4^(+)T cells and increased levels of inflammatory cytokines,including TNFα,RANKL,and IL1β.The increased levels of these cytokines significantly promote osteoclastogenesis and induce bone loss.Importantly,TLR9 deletion alters the gut microbiota,and this dysbiosis is the basis of the systemic inflammation and bone loss observed in TLR9^(-/-)mice.Furthermore,through single-cell RNA sequencing,we identified myeloid-biased hematopoiesis in the bone marrow of TLR9^(-/-)mice and determined that the increase in myelopoiesis,likely caused by the adaptation of hematopoietic stem cells to systemic inflammation,also contributes to inflammation-induced osteoclastogenesis and subsequent bone loss in TLR9^(-/-)mice.Thus,our study provides novel evidence that TLR9 signaling connects the gut microbiota,immune system,and bone and is critical in maintaining the homeostasis of inflammation,hematopoiesis,and bone metabolism under normal conditions.展开更多
基金supported by grants from the National Natural Science Foundation of China(nos.81820100820 and 81372845 to C.Z.,no.81400855 to C.Y.and no.82170893 to Q.T.)supported by National Key R&D Program of China grant no.2018YFC1106300(to C.Z.)+1 种基金Natural Science Foundation of Shanghai grant no.21ZR1448600(to C.Y.)Science and Technology Commission of Shanghai Municipality grant no.14pj1407200(to C.Y.)。
文摘Toll-like receptors(TLRs)play pivotal roles in inflammation and provide important links between the immune and skeletal systems.Although the activation of TLRs may affect osteoclast differentiation and bone metabolism,whether and how TLRs are required for normal bone remodeling remains to be fully explored.In the current study,we show for the first time that TLR9^(-/-)mice exhibit a low bone mass and low-grade systemic chronic inflammation,which is characterized by the expansion of CD4^(+)T cells and increased levels of inflammatory cytokines,including TNFα,RANKL,and IL1β.The increased levels of these cytokines significantly promote osteoclastogenesis and induce bone loss.Importantly,TLR9 deletion alters the gut microbiota,and this dysbiosis is the basis of the systemic inflammation and bone loss observed in TLR9^(-/-)mice.Furthermore,through single-cell RNA sequencing,we identified myeloid-biased hematopoiesis in the bone marrow of TLR9^(-/-)mice and determined that the increase in myelopoiesis,likely caused by the adaptation of hematopoietic stem cells to systemic inflammation,also contributes to inflammation-induced osteoclastogenesis and subsequent bone loss in TLR9^(-/-)mice.Thus,our study provides novel evidence that TLR9 signaling connects the gut microbiota,immune system,and bone and is critical in maintaining the homeostasis of inflammation,hematopoiesis,and bone metabolism under normal conditions.
