Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland.
Department of Biology, Maynooth University, Maynooth, Ireland.
FASEB J. 2023 Aug;37(8):e23072. doi: 10.1096/fj.202300787R.
Macrophage migration inhibitory factor (MIF) expression is controlled by a functional promoter polymorphism, where the number of tetranucleotide repeats (CATT ) corresponds to the level of MIF expression. To examine the role of this polymorphism in a pre-clinical model of allergic asthma, novel humanized MIF mice with increasing CATT repeats (CATT and CATT ) were used to generate a physiologically relevant scale of airway inflammation following house dust mite (HDM) challenge. CATT mice expressing high levels of human MIF developed an aggressive asthma phenotype following HDM challenge with significantly elevated levels of immune cell infiltration, production of inflammatory mediators, goblet cell hyperplasia, subepithelial collagen deposition, and airway resistance compared to wild-type controls. Importantly the potent MIF inhibitor SCD-19 significantly mitigated the pathophysiology observed in CATT mice after HDM challenge, demonstrating the fundamental role of endogenous human MIF expression in the severity of airway inflammation in vivo. Up to now, there are limited reproducible in vivo models of asthma airway remodeling. Current asthma medications are focused on reducing the acute inflammatory response but have limited effects on airway remodeling. Here, we present a reproducible pre-clinical model that capitulates asthma airway remodeling and suggests that in addition to having pro-inflammatory effects MIF may play a role in driving airway remodeling.
巨噬细胞移动抑制因子（MIF）的表达受功能启动子多态性控制，其中四核苷酸重复（CATT）的数量与 MIF 表达水平相对应。为了在过敏性哮喘的临床前模型中研究这种多态性的作用，新型具有递增 CATT 重复（CATT 和 CATT）的人源化 MIF 小鼠被用于在屋尘螨（HDM）挑战后产生与生理相关的气道炎症规模。表达高水平人 MIF 的 CATT 小鼠在 HDM 挑战后表现出侵袭性哮喘表型，与野生型对照相比，免疫细胞浸润、炎症介质产生、杯状细胞增生、上皮下胶原沉积和气道阻力显著升高。重要的是，强效 MIF 抑制剂 SCD-19 在 HDM 挑战后显著减轻了 CATT 小鼠的病理生理学变化，证明了内源性人 MIF 表达在体内气道炎症严重程度中的基本作用。到目前为止，哮喘气道重塑的可重复体内模型有限。目前的哮喘药物主要集中在减轻急性炎症反应上，但对气道重塑的影响有限。在这里，我们提出了一种可重复的临床前模型，该模型模拟了哮喘气道重塑，并表明除了具有促炎作用外，MIF 可能在驱动气道重塑方面发挥作用。
