Role of Macrophage in Osteoimmunology with Aging

项目摘要/摘要 辅助性T细胞(Th1和Th17)通过调节破骨细胞(OC)在骨稳态中发挥重要作用 自身免疫性疾病和OVX诱导的骨质疏松的形成。然而，这些T细胞如何相互作用 在老年性骨质疏松症中，骨细胞在衰老过程中破坏骨稳态，导致骨丢失 (AROP)仍然知之甚少。我们报道转化生长因子β-1(T-β-1)是导致骨丢失的主要细胞因子。 阿罗普。它诱导TRAF3的溶酶体降解，TRAF3是一种负向调节NF-κB的受体接头蛋白 在间充质祖细胞(MPC)中激活，直接抑制骨形成。然而，发布的 由于AROP骨转换率低，骨吸收来源的Tβ1活性受到限制。我们已经确定了一部小说 CD11b+F4/80+Ly6ChiLy6G-表达膜结合型T细胞β1(β1)的巨噬细胞亚群 MBTβ1MACs，其数量在老龄小鼠骨髓(BM)增加。Mbtβ1Mac也表示 ITGB8可直接激活mtβ1.mBTβ1MACs形成OCS的潜能较小，但显著抑制 成骨细胞(OB)分化。表达干扰素-γ的Th1细胞和衰老/免疫检查点PD-1也 老年小鼠的BM增加。干扰素-γ诱导Ly6chi巨噬细胞表达MBTβ1 刺激Th1细胞在体外产生干扰素-γ和PD-1，与降低TRAF3水平相关。这些影响 被FDA批准的溶酶体抑制剂羟基氯喹(HCQ)阻断。我们建议的研究将1) 确定ITGB8是否激活MBTβ1Mac中的MBTβ1，以抑制衰老过程中的骨形成；2)确定干扰素- γ使β1Mac极化，进而促进Th1细胞的衰老，促进炎症的产生 通过Tβ1诱导老年小鼠TRAF3溶酶体降解的因子；3)评估我们最近 专利骨靶向HCQ，在OVX诱导的骨质疏松症中具有抗吸收和合成代谢双重作用 模型，可通过阻断相互作用预防和治疗AROP和老年低水平慢性炎症 巨噬细胞与Th1细胞的相互作用。完成拟议的研究将确定 通过相互作用解释衰老过程中骨稳态破坏的机制 在巨噬细胞和Th1细胞之间，这种新的巨噬细胞亚群抑制骨形成和 通过刺激Th1细胞产生炎症因子，导致骨髓低水平的慢性炎症。 重要的是，它将为骨靶向HCQ可能是一种治疗AROP的新方法提供原理证据。

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.