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至关重要，但炎症偶尔会过度并在宿主中引起附带损害。这种损害可能是致命的。在这个建议中，我们专注于通过适应性免疫对过度反应的先天免疫的非常规调节。这种调节的分子机制目前是难以捉摸的和未探索的。在成功完成这项研究后，我们希望了解获得性免疫诱导先天性耐受的新机制。对机制的理解不仅对开发针对急性炎症的最佳疗法，而且对开发针对慢性炎症（包括自身免疫性疾病）的疫苗和疗法具有重大影响。 我们的初步数据表明，T细胞通过CD 40-CD 40 L相互作用抑制巨噬细胞和DC过度产生TNF。我们进一步确定，骨桥蛋白（OPN），一种主要被称为促炎分子的蛋白质，意外地在通过IRAK 1介导的IL-10产生抑制巨噬细胞中TNF表达中起调节作用。起调节作用的OPN同种型不是典型的分泌型OPN（sOPN），而是一种新的细胞内OPN同种型（iOPN）。基于我们的初步数据，本研究的中心假设是：iOPN介导巨噬细胞和DC中CD 40（由T细胞刺激）和TLR 4（由微生物配体刺激）之间的串扰，以抑制TLR 4刺激产生的TNF产生。在这个R21提案中，我们计划测试这个假设。

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.