Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon(RAP).Despite its therapeutic effects,the surgical risk and unclear mechanism hamper th...Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon(RAP).Despite its therapeutic effects,the surgical risk and unclear mechanism hamper the clinical application.Numerous evidences support macrophages as the key immune cells during bone remodeling.Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1CreERT2;R26GFP lineage tracing system.Fluorescence staining,flow cytometry analysis,and western blot determined the significantly enhanced expression of binding immunoglobulin protein(BiP)and emphasized the activation of sensor activating transcription factor 6(ATF6)in macrophages.Then,we verified that macrophage specific ATF6 deletion(ATF6f/f;CX3CR1CreERT2 mice)decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy.In contrast,macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement.In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6.At the mechanism level,RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfαpromotor and augmenting its transcription.Additionally,molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element(ERSE).Taken together,ATF6 may aggravate orthodontic bone remodeling by promoting Tnfαtranscription in macrophages,suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.展开更多
白介素1受体辅助蛋白(IL1RAP)是白介素1 (IL-1)家族的共受体,通过与白介素1受体(IL-1R)结合形成多聚复合物并激活下游信号通路发挥生物学效应。IL1RAP介导的信号通路在各类恶性肿瘤中表现出促增殖和促侵袭、迁移的特性,包括血液系统肿...白介素1受体辅助蛋白(IL1RAP)是白介素1 (IL-1)家族的共受体,通过与白介素1受体(IL-1R)结合形成多聚复合物并激活下游信号通路发挥生物学效应。IL1RAP介导的信号通路在各类恶性肿瘤中表现出促增殖和促侵袭、迁移的特性,包括血液系统肿瘤、消化道肿瘤、乳腺癌、宫颈癌等。本综述旨在阐明IL1RAP介导的信号通路的生物学效应,以及IL1RAP在各类恶性肿瘤中作用机制的研究进展。Interleukin 1 receptor accessory protein (IL1RAP) is a co-receptor of the interleukin 1 (IL-1) family, which exerts biological effects by binding to the interleukin 1 receptor (IL-1R) to form a multimeric complex and activating the downstream signaling pathway. The signaling pathway mediated by IL1RAP shows pro-proliferative, pro-invasive, and migratory properties in various types of malignant tumors, including hematological tumors, gastrointestinal tract tumors, breast cancers, cervical cancer, etc. The aim of this review is to elucidate the biological effects of IL1RAP-mediated signaling pathway and the progress of the research on the mechanism of IL1RAP in various malignant tumors.展开更多
基金supported by the National Natural Science Foundation of China(No.82160051,32100908)the Jiangxi Provincial Natural Science Foundation(No.20232BAB206018)+2 种基金the Science and Technology Research Project in the Education Department of Jiangxi Province,China(No.GJJ2200904)the Ph.D.Start-up Research Fund in Jiangxi University of Chinese Medicine(No.2020BSZR009)the Discipline of Chinese and Western Integrative Medicine in Jiangxi University of Chinese Medicine(No.zxyylxk20220103)。
基金supported by the National Natural Science Foundation of China(82071143,82371000,82270361)Key Research and Development Program of Jiangsu Province(BE2022795)+2 种基金the Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_1801)the Jiangsu Province Capability Improvement Project through the Science,Technology and Education-Jiangsu Provincial Research Hospital Cultivation Unit(YJXYYJSDW4)Jiangsu Provincial Medical Innovation Center(CXZX202227).
文摘Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon(RAP).Despite its therapeutic effects,the surgical risk and unclear mechanism hamper the clinical application.Numerous evidences support macrophages as the key immune cells during bone remodeling.Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1CreERT2;R26GFP lineage tracing system.Fluorescence staining,flow cytometry analysis,and western blot determined the significantly enhanced expression of binding immunoglobulin protein(BiP)and emphasized the activation of sensor activating transcription factor 6(ATF6)in macrophages.Then,we verified that macrophage specific ATF6 deletion(ATF6f/f;CX3CR1CreERT2 mice)decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy.In contrast,macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement.In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6.At the mechanism level,RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfαpromotor and augmenting its transcription.Additionally,molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element(ERSE).Taken together,ATF6 may aggravate orthodontic bone remodeling by promoting Tnfαtranscription in macrophages,suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.
文摘白介素1受体辅助蛋白(IL1RAP)是白介素1 (IL-1)家族的共受体,通过与白介素1受体(IL-1R)结合形成多聚复合物并激活下游信号通路发挥生物学效应。IL1RAP介导的信号通路在各类恶性肿瘤中表现出促增殖和促侵袭、迁移的特性,包括血液系统肿瘤、消化道肿瘤、乳腺癌、宫颈癌等。本综述旨在阐明IL1RAP介导的信号通路的生物学效应,以及IL1RAP在各类恶性肿瘤中作用机制的研究进展。Interleukin 1 receptor accessory protein (IL1RAP) is a co-receptor of the interleukin 1 (IL-1) family, which exerts biological effects by binding to the interleukin 1 receptor (IL-1R) to form a multimeric complex and activating the downstream signaling pathway. The signaling pathway mediated by IL1RAP shows pro-proliferative, pro-invasive, and migratory properties in various types of malignant tumors, including hematological tumors, gastrointestinal tract tumors, breast cancers, cervical cancer, etc. The aim of this review is to elucidate the biological effects of IL1RAP-mediated signaling pathway and the progress of the research on the mechanism of IL1RAP in various malignant tumors.
