Laboratory of Allergic Diseases and Inflammation, Department of Veterinary and Biomedical Sciences , Saint Paul, Minnesota.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota , Saint Paul, Minnesota.
Am J Physiol Lung Cell Mol Physiol. 2018 Aug 1;315(2):L227-L240. doi: 10.1152/ajplung.00429.2017. Epub 2018 Apr 26.
Fatty acid binding protein 4 (FABP4), a member of a family of lipid-binding proteins, is known to play a role in inflammation by virtue of its ability to regulate intracellular events such as lipid fluxes and signaling. Studies have indicated a proinflammatory role for FABP4 in allergic asthma although its expression and function in eosinophils, the predominant inflammatory cells recruited to allergic airways, were not investigated. We examined expression of FABP4 in murine eosinophils and its role in regulating cell recruitment in vitro as well as in cockroach antigen (CRA)-induced allergic airway inflammation. CRA exposure led to airway recruitment of FABP4-expressing inflammatory cells, specifically eosinophils, in wild-type (WT) mice. FABP4 expression in eosinophils was induced by TNF-α as well as IL-4 and IL-13. FABP4-deficient eosinophils exhibited markedly decreased cell spreading/formation of leading edges on vascular cell adhesion molecule-1 and significantly decreased adhesion to intercellular adhesion molecule-1 associated with reduced β2-integrin expression relative to WT cells. Furthermore, FABP4-deficient eosinophils exhibited decreased migration, F-actin polymerization, calcium flux, and ERK(1/2) phosphorylation in response to eotaxin-1. In vivo, CRA-challenged FABP4-deficient mice exhibited attenuated eosinophilia and significantly reduced airway inflammation (improved airway reactivity, lower IL-5, IL-13, TNF-α, and cysteinyl leukotriene C4 levels, decreased airway structural changes) compared with WT mice. In conclusion, expression of FABP4 in eosinophils is induced during conditions of inflammation and plays a proinflammatory role in the development of allergic asthma by promoting eosinophil adhesion and migration and contributing to the development of various aspects of airway inflammation.
脂肪酸结合蛋白 4（FABP4）是脂质结合蛋白家族的成员，已知其通过调节细胞内事件（如脂质通量和信号转导）发挥炎症作用。研究表明，FABP4 在过敏性哮喘中具有促炎作用，尽管其在嗜酸性粒细胞（招募到过敏性气道的主要炎症细胞）中的表达和功能尚未研究。我们研究了 FABP4 在鼠嗜酸性粒细胞中的表达及其在体外调节细胞募集以及蟑螂抗原（CRA）诱导的过敏性气道炎症中的作用。CRA 暴露导致野生型（WT）小鼠气道中表达 FABP4 的炎症细胞，特别是嗜酸性粒细胞的募集。TNF-α 以及 IL-4 和 IL-13 诱导嗜酸性粒细胞中 FABP4 的表达。FABP4 缺陷的嗜酸性粒细胞在血管细胞黏附分子-1 上的细胞扩散/前缘形成明显减少，与 WT 细胞相比，细胞间黏附分子-1 的黏附明显减少，与 β2-整合素表达降低有关。此外，与 WT 细胞相比，FABP4 缺陷的嗜酸性粒细胞对 eotaxin-1 的迁移、F-肌动蛋白聚合、钙通量和 ERK（1/2）磷酸化反应降低。在体内，与 WT 小鼠相比，CRA 挑战的 FABP4 缺陷小鼠表现出嗜酸性粒细胞增多减少和气道炎症明显减轻（气道反应性改善，IL-5、IL-13、TNF-α 和半胱氨酰白三烯 C4 水平降低，气道结构变化减少）。总之，在炎症条件下，FABP4 在嗜酸性粒细胞中的表达被诱导，并通过促进嗜酸性粒细胞黏附和迁移在过敏性哮喘的发展中发挥促炎作用，并有助于气道炎症的各个方面的发展。
