Regulation of innate inflammation by CD40 signaling and intracellular osteopontin

描述(由申请人提供)：适当的炎症发展对于保护宿主免受微生物感染是必不可少的，但炎症有时会过度并导致宿主的附带损害。这种损害可能是致命的。在这项建议中，我们将重点放在通过适应性免疫对过度反应的先天性免疫进行非常规调节。这种调控的分子机制目前尚不清楚，也未被探索。在这项研究成功完成后，我们希望了解获得性免疫诱导先天耐受的新机制。这一机制的理解不仅将对开发针对急性超炎症的最佳疗法，而且将对开发针对包括自身免疫性疾病在内的慢性炎症的疫苗和疗法产生重大影响。我们的初步数据表明，T细胞通过CD40-CD40L相互作用抑制巨噬细胞和DC过度产生肿瘤坏死因子。我们进一步证实，骨桥蛋白(OPN)是一种主要被认为是促炎分子的蛋白质，通过IRAK1介导的IL-10的产生，意外地在抑制巨噬细胞中的肿瘤坏死因子的表达中发挥调节作用。起调节作用的OPN亚型不是典型的分泌型OPN(SOPN)，而是一种新的细胞内OPN亚型(IOPN)。根据我们的初步数据，本研究的中心假设是：iOPN介导巨噬细胞和DC中CD40(由T细胞刺激)和TLR4(由微生物配体刺激)之间的串扰，以抑制TLR4刺激产生的TNF。在这个R21提案中，我们计划测试这一假设。

DESCRIPTION (provided by applicant): Appropriate development of inflammation is essential to protect hosts against microbial infections, but inflammation can occasionally overshoot and cause collateral damages in hosts. Such damages can be deadly. In this proposal, we focus on an unconventional regulation of over-reacted innate immunity by adaptive immunity. Molecular mechanism of such regulation is currently elusive and unexplored. Upon successful completion of this study, we expect to understand the novel mechanism by which adaptive immunity induces innate tolerance. The mechanistic understanding will have a significant impact on developing not only optimal therapies against acute hyper-inflammation but also vaccines and therapies against chronic inflammation, including autoimmune diseases. Our preliminary data suggested excessive TNF production by macrophages and DCs is suppressed by T cells through CD40-CD40L interaction. We further identified that, osteopontin (OPN), a protein largely known as a pro-inflammatory molecule, unexpectedly plays a regulatory role in suppressing TNF expression in macrophages by IRAK1-mediated IL-10 production. The OPN isotype that plays the regulatory role is not the canonical secreted OPN (sOPN) but a novel intracellular isoform of OPN (iOPN). Based on our preliminary data, the central hypothesis of this study is: iOPN mediates crosstalk between CD40 (stimulated by T cells) and TLR4 (stimulated by a microbial ligand) in macrophages and DCs to suppress TNF production generated by TLR4 stimulation. In this R21 proposal, we plan to test the hypothesis.