Innate Lymphoid Cells induce a fibrotic phenotype of fibroblasts in fibrotic diseases

先天淋巴细胞在纤维化疾病中诱导成纤维细胞的纤维化表型

• 批准号: 320379231
• 负责人: Privatdozent Dr. Andreas Ramming
• 金额: --
• 依托单位: Medizinische Klinik 3 - Rheumatologie und Immunologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/320379231?language=en
• 关键词: Innate; Lymphoid; Cells; induce; fibrotic

Fibrotic diseases impose a major socioeconomic burden on modern societies and account for up to 45% of deaths in the developed world. Despite the great medical need, anti-fibrotic therapies are not yet available for clinical use. Fibrotic diseases can affect virtually every organ system. They can be restricted to single organs, as in idiopathic pulmonary fibrosis (IPF), or may affect multiple organs, as in systemic sclerosis (SSc). SSc is a prototypic multisystem fibrotic disorder that disrupts the physiological architecture of affected tissue by an excessive accumulation of extracellular matrix. The current concept of the pathogenesis of multisystem fibrotic diseases postulates a triad of inflammation attributed to humoral and cellular immune abnormalities, vasculopathy and fibrosis. However, the mechanisms in this fundamentally important process of tissue injury are incompletely understood. Fibrotic diseases and normal wound healing share a common tissue repair response in the initial stages. This common repair response is characterized by an inflammatory reaction with leukocyte infiltration into the affected tissues. The release of pro-inflammatory and pro-fibrotic mediators from these infiltrating leukocytes activates fibroblasts and stimulates the release of collagen and other components of the extracellular matrix. Fibrotic diseases fail to efficiently terminate this repair program. In normal wound healing, inflammation and fibroblast activation are limited to the site of injury and are turned-off right after appropriate repair. A growing body of evidence suggests that overproduction of extracellular matrix components results from complex interactions between various cells, including leukocytes and fibroblasts. More recently, locally accumulating innate-like lymphoid cells (ILCs) are emerging as an important cellular source of cytokines triggering fibrotic tissue remodeling independently of the adaptive immune system. Therefore, we aim to further characterize ILCs and to validate ILC2s as therapeutic target in fibrotic diseases.

纤维性疾病给现代社会造成了重大的社会经济负担，占发达国家死亡人数的45%。尽管医学上有很大的需求，但抗纤维化疗法还不能用于临床。纤维性疾病几乎可以影响到每个器官系统。它们可以局限于单个器官，如特发性肺纤维化(IPF)，或可能累及多个器官，如系统性硬化症(SSC)。SSC是一种典型的多系统纤维化疾病，通过细胞外基质的过度积聚扰乱受影响组织的生理结构。目前关于多系统纤维化疾病的发病机制的概念假设为三重炎症，归因于体液和细胞免疫异常、血管病变和纤维化。然而，在这一重要的组织损伤过程中的机制还不完全清楚。纤维性疾病和正常的伤口愈合在最初阶段有共同的组织修复反应。这种常见的修复反应的特点是炎症反应，白细胞渗透到受影响的组织中。从这些渗入的白细胞释放促炎和促纤维化介质，激活成纤维细胞，刺激细胞外基质的胶原和其他成分的释放。纤维性疾病不能有效地终止这一修复计划。在正常的伤口愈合中，炎症和成纤维细胞的激活仅限于损伤部位，并在适当的修复后立即关闭。越来越多的证据表明，细胞外基质成分的过度产生是各种细胞之间复杂相互作用的结果，包括白细胞和成纤维细胞。最近，局部聚集的先天类淋巴样细胞(ILCs)正在成为一种重要的细胞因子来源，触发纤维组织重塑，而不依赖于适应性免疫系统。因此，我们的目标是进一步确定ILC的特征，并验证ILC2s作为纤维化疾病的治疗靶点。