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：
Zhenqiang Yao
金额：
$ 44.19万
依托单位：
UNIVERSITY OF ROCHESTER
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：
https://reporter.nih.gov/project-details/10612437
关键词：
Adaptor Signaling Protein Age Age-Related Bone Loss Age-Related Osteoporosis Aging Attenuated Autoimmune Diseases Binding Biological Bone Formation Inhibition Bone Formation Stimulation Bone Marrow Bone Resorption Bone Resorption Inhibition CD4 Positive T Lymphocytes CXCR3 gene Cell Aging Cell Communication Cell physiology Cell surface Cells Chemicals Chronic Coupled Enterobacteria phage P1 Cre recombinase FDA approved Helper-Inducer T-Lymphocyte Homeostasis Hydroxychloroquine IFNGR1 gene ITGAM gene Immune In Vitro Inflammaging Inflammation Inflammatory Integrin beta Chains Interferon Type II Interleukin-12 Interleukin-2 Knock-out Legal patent Link Macrophage Maps Mediating Membrane Mesenchymal Stem Cells Modeling Molecular Mus Osteoblasts Osteoclasts Osteogenesis Osteoporosis Osteoporotic Play Production Proteins Reporting Role Surface T-Cell Activation T-Lymphocyte TNF receptor-associated factor 3 TNFSF11 gene Testing Th1 Cells Transforming Growth Factor beta aged bisphosphonate bone bone cell bone loss bone turnover chemokine cytokine immune checkpoint inhibitor novel novel strategies osteoblast differentiation osteoimmunology prevent programmed cell death protein 1 promoter receptor senescence transcriptomics

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.

项目摘要/摘要 T辅助细胞（Th1和Th17）在调节破骨细胞（OC）的骨稳态中起重要作用但是，自身免疫性疾病和OVX诱导的骨质疏松症。骨细胞在导致与年龄有关的骨质疏松症引起骨质流失期间破坏骨稳态（AROP）仍然很了解TGFβ1（Tβ1）是主要引起骨损失的细胞因子 AROP。激活，在间充质祖细胞（MPC）中直接吸入骨骼由于远射量低的骨头转换，从吸收骨骼中的活性Tβ1受到限制。表达膜结合Tβ1（MBTβ1）的CD11b+F4/80+ly6chily6g巨噬细胞的子集，我们carl MBTβ1MAC，其数量在老年小鼠的骨髓（BM）中增加。可以直接激活MTβ1的ITGB8。成骨细胞（OB）分化。 IFN-γ的BM增加。刺激在体外产生IFN-γ和PD-1的Th1细胞，与TRAF3的水平降低有关被FDA认可的溶酶体抑制剂阻塞，羟氯喹（HCQ）。确定ITGB8是否激活MBTβ1MAC中的MBTβ1在衰老过程中抑制骨形成； γ极化MBTβ1MAC，这又促进了Th1细胞的炎症产生通过Tβ1指示型老鼠的Traf3溶酶体降解的因素；获得专利的骨头靶向HCQ，在OVX诱导的骨质疏松术中具有双抗储备和合成代谢作用模型，可以通过阻止倒数，可以证明并信任arop arop and arop arop and低低慢性炎症。巨噬细胞和Th1细胞之间的相互作用。解释通过相互作用衰老期间骨稳态破坏的机制在巨噬细胞和Th1细胞之间，这是巨噬细胞的这一抑制骨骼形成和通过刺激TH1细胞产生炎症因子，导致BM低级慢性炎症。重要的是，它将提供原理证明，即骨靶向HCQ可能是AROP的新型治疗方法。