Dysregulated Immunometabolism and Premature Senescence in Corticosteroid-Refractory Severe Asthma

本实验室从事哮喘发病机制的研究已有二十多年。 这些努力导致发现加塔-3作为Th 2细胞发育的关键分子调节剂 会导致过敏性气道疾病自我们最初发现以来，加塔-3已成功靶向过敏原- 导致人类轻度哮喘。虽然Th 2驱动的轻度哮喘是公认的， 在使用吸入性皮质类固醇（CS）可管理的情况下，5-10%的哮喘在临床上被认为是严重的，并且这些患者 即使大剂量使用，对CS的反应也很差。为了解决疾病异质性的问题， 为了明确潜在的机制，我们研究了严重哮喘（SA）患者气道免疫细胞 使用免疫学和分子生物学的各种工具，包括高维多组学方法。 我们已经使用我们实验室建立的新的SA小鼠模型来验证潜在的靶点 用于体内治疗干预。这些研究导致了另一个原始的和意想不到的发现， SA患者支气管肺泡灌洗（BAL）T细胞中的IFN-γ应答（1型/T1应答）， 这些T细胞的大部分具有组织驻留记忆T细胞（TRM）的特征。A T1高免疫 在独立研究中，儿童和成人的SA反应越来越受到重视 挑战了IFN-g在哮喘中总是保护性的信念，因为它交叉调节T2免疫应答。 我们还确定了一个有害的前馈正循环引起的CS由于合作之间 STAT 1，IFN-γ的下游，和糖皮质激素受体（GR），这将导致持续的IFN-γ 在航空公司生产。持续产生干扰素-g的后果可能是深远的和有害的 因为它有诱导细胞衰老的潜力。与T1 high免疫应答密切相关的是， 细胞代谢，因为线粒体功能障碍导致高水平的IFN-γ产生。新兴 文献提供了免疫细胞中线粒体功能障碍导致衰老的有力证据， 发炎虽然复制性衰老和炎症通常与老年有关，但这种概念 压力诱导的过早衰老（SIPS）导致过早衰老和衰老的观点正在受到关注， 肺疾病，包括特发性肺纤维化（IPF）和慢性阻塞性肺疾病（COPD）。 由于IFN-g可诱导周围细胞衰老，SIPS的驱动因素可能是炎症免疫。 细胞，尤其是T1高TRM。拟议的研究计划的主要目标是询问肺和 外周血免疫细胞和脂质在患者的BAL液，以确定机制，诱导CS- SA中的难治性炎症表型。我们相信我们的研究将确定新的治疗靶点， 预防可能与其他肺部疾病相关的SA中的SIPS。长期供资和灵活性 R35机制将帮助我继续培养新一代的科学家， 免疫功能障碍，以开发新的治疗方法，治疗可诱导SIPS的顽固性慢性肺部疾病。

Our laboratory has been engaged in elucidating mechanisms of asthma pathogenesis for over two decades. These efforts resulted in the discovery of GATA-3 as the key molecular regulator of development of Th2 cells that promote allergic airway disease. Since our initial discovery, GATA-3 was successfully targeted in allergen- induced mild asthma in humans. While Th2-driven mild asthma is well recognized and therapeutically manageable with inhaled corticosteroids (CS), 5-10% of asthma is clinically deemed severe and these patients poorly respond to CS, even when used in large doses. To address this issue of disease heterogeneity and identify the underlying mechanisms, we have studied the airway immune cells of severe asthma (SA) patients using various tools of immunology and molecular biology including a high dimensional multi-omics approach. Side-by-side we have used new mouse models of SA established in our laboratory to validate potential targets for therapeutic intervention in vivo. These studies have led to another original and unexpected finding of a high IFN-g response (Type 1/T1 response) in bronchoalveolar lavage (BAL) T cells in a subset of SA patients, a large fraction of these T cells having features of tissue resident memory T cells (TRMs). A T1high immune response is increasingly being appreciated in SA in both children and adults in independent studies challenging the belief that IFN-g is always protective in asthma since it cross-regulates a T2 immune response. We have also identified a deleterious feed forward positive loop induced by CS due to co-operation between STAT1, downstream of IFN-g, and the glucocorticoid receptor (GR) that would cause unremitting IFN-g production in the airways. The ramifications of unremitting IFN-g production can be profound and damaging given its potential to induce cellular senescence. Intimately associated with the T1high immune response is also cellular metabolism since mitochondrial dysfunction results in high levels of IFN-g production. Emerging literature provides strong evidence of mitochondrial dysfunction in immune cells resulting in senescence and inflammaging. While replicative senescence and inflammaging are typically associated with old age, the notion of stress-induced premature senescence (SIPS) causing premature aging and decline is being entertained in lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Since IFN-g can induce senescence in surrounding cells, the driver of SIPS may be inflammatory immune cells, especially T1high TRMs. The key goal of the proposed research program is to interrogate lung and peripheral blood immune cells and lipids in the BAL fluid of patients to identify mechanisms that induce a CS- refractory inflammatory phenotype in SA. We believe our studies would identify novel therapeutic targets to prevent SIPS in SA which may have relevance in other lung diseases. The long-term funding and flexibility of the R35 mechanism will help me to continue to train a new generation of scientists interested in studying immune dysfunction to develop novel therapies for recalcitrant chronic lung diseases that can induce SIPS.