Immunomodulatory function of inflammasomes in human primary dendritic cells

人原代树突状细胞炎症小体的免疫调节功能

• 批准号: 515982377
• 负责人: Professorin Dr. Diana Dudziak
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/515982377?language=en
• 关键词: Immunomodulatory; function; inflammasomes; human; primary

Dendritic cells (DCs) play a pivotal role in orchestrating immune responses. Equipped with various receptors in the membrane, DCs sense the tissue microenvironment for danger signals and pathogens. Inflammasomes play a pivotal role in the immune response against certain pathogens, but also in the pathogenesis of inflammatory disorders and cancer. The formation of this multiprotein signaling complex requires a TLR-mediated initial priming step and a second activation step leading to the secretion of the bioactive cytokines. Usually, the activation of the inflammasome induces pyroptosis, an inflammatory cell death mediated by the activation of caspase-1. Previously, we could show that human cDC2 can enter a state of hyperactivation, which is characterized by inflammasome activation in the absence of pyroptosis. For human cDC2, two subpopulations, namely DC2 and DC3, with so far unclear functional specialization have been recently described. Our preliminary data suggest that DC2 and DC3 differ in their response to hyperactivating inflammasome ligands. Moreover, we have hints that in human breast cancer biopsies the ratio of DC2 to DC3 is associated with certain breast cancer subtypes, indicating a subset specific function in tumor control. Further, the inflammasome ligand oxPAPC, a mixture of oxidized phospholipids, induced a rather immunosuppressive phenotype in human cDC2. Such oxidized phospholipids have been identified in tumors underlining a potential role in the immunosuppression of cDC2 subsets. We here hypothesize that DC2 and DC3 exert different roles in the polarization of immune responses in dependency on the inflammasome stimulus. Understanding the inflammasome-mediated immunomodulation is important for advancing therapies for tumors and autoimmune diseases. In the here proposed project, we will focus on the functional characterization of the two human primary cDC2 subpopulations. We further will study the regulation of hyperactivation versus tolerance/immunosuppression in the human DC subpopulations.

树突状细胞（DC）在协调免疫应答中起着关键作用。树突状细胞在细胞膜上配备了各种受体，可以感知组织微环境中的危险信号和病原体。炎性小体在针对某些病原体的免疫应答中起关键作用，而且在炎性病症和癌症的发病机制中也起关键作用。这种多蛋白信号传导复合物的形成需要TLR介导的初始引发步骤和导致生物活性细胞因子分泌的第二活化步骤。通常，炎性小体的活化诱导焦亡，一种由半胱天冬酶-1的活化介导的炎性细胞死亡。以前，我们可以表明，人cDC 2可以进入一个超活化状态，其特征是在没有焦亡的情况下炎性小体活化。对于人cDC 2，最近描述了两个亚群，即DC 2和DC 3，迄今为止功能特化不清楚。我们的初步数据表明，DC 2和DC 3不同，他们的反应过度活化炎性体配体。此外，我们有线索表明，在人类乳腺癌活检中，DC 2与DC 3的比例与某些乳腺癌亚型相关，表明肿瘤控制中的亚组特异性功能。此外，炎性体配体oxPAPC，氧化磷脂的混合物，诱导人cDC 2中的免疫抑制表型。已经在肿瘤中鉴定了这种氧化磷脂，强调了cDC 2亚群免疫抑制的潜在作用。 我们在此假设DC 2和DC 3在依赖于炎性小体刺激的免疫应答极化中发挥不同的作用。了解炎性小体介导的免疫调节对于推进肿瘤和自身免疫性疾病的治疗具有重要意义。在这里提出的项目中，我们将集中在两个人的主要cDC 2亚群的功能特性。我们将进一步研究人类DC亚群中超活化与耐受/免疫抑制的调节。