Role of Macrophage in Osteoimmunology with Aging
巨噬细胞在衰老骨免疫学中的作用
基本信息
- 批准号:10612437
- 负责人:
- 金额:$ 44.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinAgeAge-Related Bone LossAge-Related OsteoporosisAgingAttenuatedAutoimmune DiseasesBindingBiologicalBone Formation InhibitionBone Formation StimulationBone MarrowBone ResorptionBone Resorption InhibitionCD4 Positive T LymphocytesCXCR3 geneCell AgingCell CommunicationCell physiologyCell surfaceCellsChemicalsChronicCoupledEnterobacteria phage P1 Cre recombinaseFDA approvedHelper-Inducer T-LymphocyteHomeostasisHydroxychloroquineIFNGR1 geneITGAM geneImmuneIn VitroInflammagingInflammationInflammatoryIntegrin beta ChainsInterferon Type IIInterleukin-12Interleukin-2Knock-outLegal patentLinkMacrophageMapsMediatingMembraneMesenchymal Stem CellsModelingMolecularMusOsteoblastsOsteoclastsOsteogenesisOsteoporosisOsteoporoticPlayProductionProteinsReportingRoleSurfaceT-Cell ActivationT-LymphocyteTNF receptor-associated factor 3TNFSF11 geneTestingTh1 CellsTransforming Growth Factor betaagedbisphosphonatebonebone cellbone lossbone turnoverchemokinecytokineimmune checkpointinhibitornovelnovel strategiesosteoblast differentiationosteoimmunologypreventprogrammed cell death protein 1promoterreceptorsenescencetranscriptomics
项目摘要
Project Summary/Abstract
T helper cells (Th1 and Th17) play an important role in bone homeostasis through regulating osteoclast (OC)
formation in autoimmune diseases and OVX-induced osteoporosis. However, how these T cells interactions
with bone cells disrupt bone homeostasis during aging to cause bone loss in age-related osteoporosis
(AROP) remains poorly understood. We reported that TGFβ1 (Tβ1) is a major bone loss-causing cytokine in
AROP. It induces lysosomal degradation of TRAF3, a receptor adaptor protein that negatively regulates NF-κB
activation, in mesenchymal progenitor cells (MPCs) to directly inhibit bone formation. However, the release of
active Tβ1 from resorbing bone is limited because of low bone turnover in AROP. We have identified a novel
subset of CD11b+F4/80+Ly6ChiLy6G- macrophages expressing membrane-bound Tβ1 (mbTβ1), which we call
MbTβ1Macs, whose numbers are increased in the bone marrow (BM) of aged mice. MbTβ1Macs also express
ITGB8 which can directly activate mTβ1. MbTβ1Macs have less potential to form OCs, but significantly inhibit
osteoblast (OB) differentiation. Th1 cells expressing IFN-γ and senescent/immune checkpoint PD-1 are also
increased in the BM of aged mice. IFN-γ induces Ly6Chi macrophages to express mbTβ1, which in turn
stimulates Th1 cells producing IFN-γ and PD-1 in vitro, associated with reduced levels of TRAF3. These effects
are blocked by the FDA approved lysosomal inhibitor, hydroxychloroquine (HCQ). Our proposed studies will 1)
determine if ITGB8 activates mbTβ1 in MbTβ1Macs to inhibit bone formation during aging; 2) determine if IFN-
γ polarizes MbTβ1Macs, which in turn promote Th1 cell senescence with enhanced production of inflammatory
factors via Tβ1 induction of TRAF3 lysosomal degradation in aged mice; and 3) evaluate if our recently
patented bone-targeted HCQ, with dual anti-resorptive and anabolic effects in an OVX-induced osteoporotic
model, can prevent and treat AROP and low level chronic inflammation during age by blocking the reciprocal
interactions between macrophages and Th1 cells. Completion of the proposed studies will identify novel
mechanisms to explain the disruption of bone homeostasis during aging through reciprocal interactions
between macrophages and Th1 cells, in which this novel subset of macrophages inhibits bone formation and
causes BM low-level chronic inflammation by stimulating Th1 cells to produce inflammatory factors.
Importantly, it will provide proof of principle that a bone-targeted HCQ may be a novel treatment for AROP.
项目总结/摘要
辅助性T细胞(Th 1和Th 17)通过调节破骨细胞(OC)在维持骨平衡中发挥重要作用。
在自身免疫性疾病和OVX诱导的骨质疏松症中的形成。然而,这些T细胞如何相互作用
随着骨细胞在衰老过程中破坏骨稳态,导致与年龄相关的骨质疏松症中的骨丢失
(AROP)仍然知之甚少。我们报道了TGFβ1(Tβ1)是一种引起骨丢失的主要细胞因子,
AROP。它诱导TRAF 3的溶酶体降解,TRAF 3是一种负调节NF-κB的受体衔接蛋白
活化,在间充质祖细胞(MPC)中直接抑制骨形成。然而,释放
由于AROP中骨转换率低,来自再吸收骨的活性Tβ1有限。我们发现了一本小说
表达膜结合Tβ1(mbTβ1)的CD 11b +F4/80+ Ly 6ChiLy 6 G-巨噬细胞亚群,我们称之为
MbTβ 1 Macs在老年小鼠骨髓中的数量增加。MbTβ 1 Macs还表达
ITGB 8可直接激活mTβ1。MbTβ 1 Macs形成OC的能力较低,但能显著抑制OC的形成。
成骨细胞(OB)分化。表达IFN-γ和衰老/免疫检查点PD-1的Th 1细胞也被激活。
在老年小鼠的BM中增加。IFN-γ诱导Ly 6Chi巨噬细胞表达mbTβ1,
在体外刺激Th 1细胞产生IFN-γ和PD-1,与TRAF 3水平降低相关。这些影响
被FDA批准的溶酶体抑制剂羟氯喹(HCQ)阻断。我们建议的研究将1)
确定ITGB 8是否激活MbTβ 1 Macs中的mbTβ1以抑制衰老过程中的骨形成; 2)确定IFN-γ是否激活MbTβ 1 Macs中的mbTβ 1以抑制衰老过程中的骨形成。
γ极化MbTβ 1 Macs,这反过来又促进Th 1细胞衰老,增加炎性细胞因子的产生。
通过Tβ1诱导老年小鼠TRAF 3溶酶体降解的因素; 3)评估我们最近的研究结果,
获得专利的骨靶向HCQ,在OVX诱导的骨质疏松症中具有双重抗吸收和合成代谢作用,
模型,可通过阻断AROP和低水平慢性炎症的相互作用,
巨噬细胞和Th 1细胞之间的相互作用。完成拟议的研究将确定新的
通过相互作用解释衰老过程中骨稳态破坏的机制
巨噬细胞和Th 1细胞之间,其中这种新型巨噬细胞亚群抑制骨形成,
通过刺激Th 1细胞产生炎症因子引起BM低水平慢性炎症。
重要的是,它将提供骨靶向HCQ可能是AROP的新治疗方法的原则证据。
项目成果
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Zhenqiang Yao其他文献
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{{ truncateString('Zhenqiang Yao', 18)}}的其他基金
Role of Macrophage in Osteoimmunology with Aging
巨噬细胞在衰老骨免疫学中的作用
- 批准号:
10429733 - 财政年份:2022
- 资助金额:
$ 44.19万 - 项目类别:
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