2型免疫在组织修复和纤维化中的作用

2型免疫的特征在于产生IL-4，IL-5，IL-9和IL-13，并且这种免疫应答通常在变态反应性炎症或蠕虫寄生虫感染期间在组织中观察到。然而，许多与2型免疫反应相关的关键细胞类型 - 包括T辅助细胞2，嗜酸性粒细胞，肥大细胞，嗜碱性粒细胞，2型先天淋巴细胞和IL-4和IL-13激活的巨噬细胞 - 也调节组织修复受伤后的反应。事实上，这些细胞群体通过减少组织炎症和激活重要的组织再生机制来进行关键的保护性活动。然而，当2型细胞因子介导的修复过程变成慢性，过度旺盛或失调时，它们也可以促成许多不同器官系统中病理性纤维化的发展。 在这篇综述中，我们讨论了2型免疫对损伤后组织再生和纤维化有帮助的机制。

Type 2 immunity is characterized by the production of IL-4, IL-5, IL-9 and IL-13, and this immune response is commonly observed in tissues during allergic inflammation or infection with helminth parasites. However, many of the key cell types associated with type 2 immune responses - including T helper 2 cells, eosinophils, mast cells, basophils, type 2 innate lymphoid cells and IL-4- and IL-13-activated macrophages - also regulate tissue repair following injury. Indeed, these cell populations engage in crucial protective activity by reducing tissue inflammation and activating important tissue-regenerative mechanisms. Nevertheless, when type 2 cytokine-mediated repair processes become chronic, over-exuberant or dysregulated, they can also contribute to the development of pathological fibrosis in many different organ systems. In this Review, we discuss the mechanisms by which type 2 immunity contributes to tissue regeneration and fibrosis following injury.

2型免疫的特征在于细胞因子IL-4，IL-5，IL-9和IL-13的生成增加（参考文献1）。 T辅助者1（T ^ H1）和T ^ H2范例在大约三十年前首次被描述，并且对于许多干预年，2型免疫主要被认为是控制1型免疫的简单反调控机制（BOX 1 ）。 早期研究表明，当2型反应的组分被消除时，由于1型驱动的炎症失调，一般对多种自身免疫疾病的易感性增加。今天，我们对2型细胞因子在宿主免疫和炎症疾病中的多种作用的理解变得越来越清楚，2型免疫在取决于特定环境下表现出宿主保护或致病活性。除了抑制1型和T ^ H17驱动的炎症之外，2型免疫还直接参与损伤后的组织修复和再生，许多研究表明IL-4和IL-13激活的巨噬细胞在决议中的关键作用炎症和组织稳态的恢复。 调节由2型细胞因子和表征2型炎症的其他细胞类型激活的巨噬细胞（包括嗜酸性粒细胞，肥大细胞，嗜碱性粒细胞，T ^ H 2细胞和2组先天淋巴细胞（ILC2））的组织修复的具体机制仍未明确。 而且，虽然2型免疫有助于恢复损伤后的组织内稳态，但2型免疫应答也可导致病理性纤维化的发展（图1）。尽管组织修复途径的持续激活在大多数情况下是主要的促成机制，但是将这些组织再生型2型应答转化为进行性纤维化疾病的机制仍不清楚。在本综述中，我们简要概述了与激活2型免疫有关的纤维化疾病，讨论了促成2型炎症发生和维持的各种机制，并探讨了这些途径可能成为长期激活的方式或失调。我们强调调节2型依赖性修复和纤维化反应的关键细胞类型，并说明2型细胞因子与其他关键介质相互作用以指导组织修复的机制，以及这些途径如何在失调时导致纤维化发展。

Type 2 immunity is characterized by increased production of the cytokines IL-4, IL-5, IL-9 and IL-13 (REF. 1). The T helper 1 (T^H1) and T^H2 paradigm was first described approximately three decades ago, and for many of the intervening years, type 2 immunity was largely considered as a simple counter-regulatory mechanism controlling type 1 immunity (BOX 1). Early studies showed that when components of the type 2 response were ablated, susceptibility to a variety of autoimmune diseases generally increased due to dysregulated type 1-driven inflammation. Today, our understanding of the diverse roles of type 2 cytokines in host immunity and inflammatory disease is becoming clearer, with type 2 immunity exhibiting either host-protective or pathogenic activity depending on the specific setting. In addition to suppressing type 1- and T^H17-driven inflammation, type 2 immunity is directly involved in tissue repair and regeneration following injury, with many studies suggesting critical roles for IL-4- and IL-13-activated macrophages in the resolution of inflammation and restoration of tissue homeostasis. The specific mechanisms regulating tissue repair by macrophages activated by type 2 cytokines and other cell types that characterize type 2 inflammation, including eosinophils, mast cells, basophils, T^H2 cells and group 2 innate lymphocytes (ILC2s), remain ill defined. Moreover, while type 2 immunity helps to restore tissue homeostasis following injury, type 2 immune responses can also lead to the development of pathological fibrosis (FIG. 1). The mechanisms that transform these tissue-regenerative type 2 responses into progressive fibrotic disorders remain unclear, although persistent activation of tissue repair pathways is a major contributing mechanism in most cases. In this Review, we provide a brief overview of fibrotic diseases that have been linked to activation of type 2 immunity, discuss the various mechanisms that contribute to the initiation and maintenance of type 2 inflammation and examine the ways in which these pathways may become chronically activated or dysregulated. We highlight the key cell types that regulate type 2-dependent repair and fibrosis responses and illustrate both the mechanisms through which type 2 cytokines interact with other key mediators to instruct tissue repair and how these pathways contribute to the development of fibrosis when dysregulated.

未来的方向和机会：鉴于证明2型免疫的促纤维化性质以及特别是当持续活化时IL-4和IL-13信号传导的广泛证据，这种类型的免疫应答已被证明对各种过敏性和纤维化过程中的治疗调节具有吸引力疾病。几个研究组正在研究或正在积极研究使用单独或联合使用双功能或双特异性策略靶向IL-4和IL-13信号通路不同方面的抗体和/或拮抗剂进行阻断。 这些试验在各种疾病中的结果是混合的，并且在一些情况下，与对照组相比，试验已经显示接受治疗的患者的结果恶化。

Given the extensive evidence demonstrating the pro-fibrotic nature of type 2 immunity and, in particular, IL-4 and IL-13 signalling when continuously activated, this type of immune response has proven attractive for therapeutic modulation during the course of various allergic and fibrotic diseases. Several groups have investigated or are actively investigating blockade using antibodies and/or antagonists targeting various aspects of the IL-4 and IL-13 signalling pathways alone or in combination using bifunctional or bi-specific strategies. The results of such trials in various diseases have been mixed, and in some cases, the trials have demonstrated worsened outcomes in patients receiving treatment compared with control arms.

如前所述，已经显示几种1型细胞因子可以反式调节2型免疫。然而，2型细胞因子也是1型和T ^ H17驱动的炎症反应的重要调节剂。最近，一些研究显示阻断2型细胞因子可以使这种交叉调节机制失调并促进1型和T17H17驱动的炎症，加剧IFNγ和IL-17A驱动的细胞毒性损伤。在实验鼠血吸虫病和肺肉芽肿模型的过程中，单独阻断IL-13显着减少纤维化，但同时导致IFNγ产生增加和随后的TNF产生和炎性组织坏死增加，加重肝脏和肺损伤。然而，IL-13和IFNγ的双重阻断导致纤维化的显着减少，并消除了在仅用抗IL-13处理的小鼠中观察到的反弹1型炎症和相关损伤。类似地，已经显示在HDM诱导的变态反应模型中阻断IL-4和/或IL-13诱导大量T ^ H17细胞驱动的嗜中性粒细胞炎症;然而，双重阻断IL-13和IL-17A保护小鼠免受嗜酸性粒细胞和嗜中性粒细胞炎症，并消除相关的粘液产生和气道高反应性，说明双重或多重阻滞战略对付反弹炎症的益处（图5）。有趣的是，推测在阻断IL-4和/或IL-13信号传导途径的方面的临床试验中观察到的一些令人失望的结果可能是1型和TβH17驱动的炎症反应的无意失调的结果和/或破坏IL-4和IL-13信号传导的重要有益方面，例如上皮再生。 总之，这些研究表明，小心地靶向和给药治疗剂将是必要的，以成功地阻断持续型2驱动的炎症的致病特征而不牺牲伤口修复和上皮再生的有益特征或对患者进行潜在的有害反弹炎症反应。揭示维持促纤维化信号和抑制内源性机制以终止伤口愈合反应的各种细胞，分子和遗传机制将是未来几年的重要研究目标。

As stated earlier, several type 1 cytokines have been shown to counter-regulate type 2 immunity. However, type 2 cytokines are also important regulators of type 1- and T^H17-driven inflammatory responses. Recently, several studies have revealed that blockade of type 2 cytokines can dysregulate this cross-regulatory mechanism and promote type 1- and T^H17-driven inflammation, exacerbating IFNγ- and IL-17A-driven cytotoxic injury. During the course of experimental murine schistosomiasis and in pulmonary granuloma models, blocking IL-13 alone significantly reduces fibrosis but concurrently leads to increases in IFNγ production and subsequent increases in TNF production and inflammatory tissue necrosis, exacerbating liver and lung damage. However, dual blockade of IL-13 and IFNγ led to a marked reduction in fibrosis and eliminated the rebound type 1 inflammation and associated damage observed in mice treated with anti-IL-13 alone. Similarly, it has been shown that blockade of IL-4 and/or IL-13 in HDM-induced allergy models induces substantial T^H17 cell-driven neutrophilic inflammation; however, dual blockade of IL-13 and IL-17A protected mice from both eosinophilic and neutrophilic inflammation and eliminated associated mucus production and airway hyperreactivity, illustrating the benefits of dual- or multi-blockade strategies to combat rebound inflammation (FIG. 5). It is interesting to speculate that some of the disappointing outcomes observed in clinical trials blocking aspects of the IL-4 and/or IL-13 signalling pathways may be the result of unintended dysregulation of the type 1- and T^H17-driven inflammatory responses and/or disruption of important beneficial aspects of IL-4 and IL-13 signalling, such as epithelial regeneration. Together, these studies suggest that careful targeting and dosing of therapeutics will be necessary to successfully block the pathogenic features of sustained type 2-driven inflammation without sacrificing the beneficial features of wound repair and epithelial regeneration or subjecting patients to potentially harmful rebound inflammatory responses. Uncovering the various cellular, molecular and genetic mechanisms that sustain pro-fibrotic signalling and inhibit endogenous mechanisms to end wound healing responses will be an important research goal in the coming years.