The migratory and functional contribution of pleural space immune cells during inflammation and cancer

在创伤、炎症和癌症期间，体腔中的免疫细胞池会导致与疾病相关的损害。在肝损伤期间，腹膜巨噬细胞重新定位到肝实质以诱导有效的组织修复，而胸膜腔固有反应激活物(IRA)B细胞渗入肺以保护其免受呼吸道感染。尽管这些机制提示浆膜腔免疫细胞在炎症和癌症中发挥重要作用，但其他胸膜间隙细胞在细菌或病毒肺部感染的免疫反应中的免疫作用，它们在介导先天获得性免疫反应中的功能以及其他胸膜间隙细胞在肺癌疾病中的作用仍很不清楚。在过去的几年里，我们(I)阐明了胸腔IRA B细胞在第二阶段气道炎症中的作用；(Ii)探索了通过其他各种细胞外和细胞内介质(TLR1/2/4/9；IRAK4)产生IRA B细胞；(Iii)研究了稳定期和炎症条件下胸腔细胞的运输；以及(Iv)分析了依赖GM-CSF的肺巨噬细胞在肺肿瘤模型中抗体介导免疫治疗中的作用。我们的结果表明：(1)IRA B细胞在细菌肺部感染时影响肺和引流淋巴结中树突状细胞(DC)和T细胞的数量；(2)IRAK4介导IRA B细胞的发育；(3)胸腔在肺部炎症时是T细胞的细胞中心；(4)GM-CSF的产生是巨噬细胞介导的抗肿瘤抗体活性的重要特征。这导致了几个新的和重要的问题，这些问题是本提案的重点。为了研究胸膜腔T细胞在先天性和获得性免疫反应中的作用，我们将进行转运和功能分析。从机制上，我们将探讨肿瘤坏死因子在产生α的壁胸膜细胞以及IRA B细胞对T细胞迁移和功能的作用，以有效地保护肺部炎症。在结直肠癌肺转移模型和肺癌异种移植模型中，我们将研究胸膜腔(IRA)B细胞和巨噬细胞在肿瘤发生发展中的作用。

The immune cell pool in the body cavities contribute to disease related damages during trauma, inflammation and cancer. Peritoneal macrophages relocate into the liver parenchyma during liver injury to induce potent tissue repair while pleural space innate response activator (IRA) B cells extravasate into the lungs to protect against airway infection. Although these mechanisms suggest an important function of serosal cavity immune cells during inflammation and cancer, the immunological role of other pleural space cells in the immune response to bacterial or viral lung infections, their function in mediating innate into adaptive immune responses as well as the role of other residing pleural space cells during lung cancer disease remain largely unknown. Within the last years we (i) elucidated the function of pleural space IRA B cells in the second phase of airway inflammation; (ii) explored the generation of IRA B cells through various other extra- and intracellular mediators (TLR 1/2/4/9; IRAK4); (iii) investigated the trafficking of pleural space cells during steady state and inflammatory conditions; and (iv) analyzed the impact of GM-CSF dependent lung macrophages for antibody mediated immunotherapy in a lung tumor model. Our results indicate that (i) IRA B cells influence the amount of dendritic cells (DCs) and T cells in the lungs and draining lymph nodes during bacterial lung infection; that (ii) IRAK4 mediates the development of IRA B cells; that (iii) the pleural space serves as a cellular hub for T cells during lung inflammation; and that (iv) GM-CSF production is an important feature for macrophage mediated anti-tumor antibody activity. This leads to several new and important questions that are in the focus of this proposal. To investigate the role of pleural space T cells in the innate and adaptive immune responses we will conduct trafficking and functional analysis. Mechanistically, we will explore the role of tumor necrosis factor α-producing parietal pleural membrane cells as well as IRA B cells on T cell migration and function for effective protection during lung inflammation. In a model of colorectal cancer lung metastasis as well as in a xenograft model for primary lung cancer we will investigate the impact of pleural space (IRA) B cells and macrophages in tumor development and progression.