Retnla Overexpression Attenuates Allergic Inflammation of the Airway

Resistin-like molecule alpha (Retnla), also known as ‘Found in inflammatory zone 1’, is a secreted protein that has been found in bronchoalveolar lavage (BAL) fluid of ovalbumin (OVA)-induced asthmatic mice and plays a role as a regulator of T helper (Th)2-driven inflammation. However, the role of Retnla in the progress of Th2-driven airway inflammation is not yet clear. To better understand the function of Retnla in Th2-driven airway inflammation, we generated Retnla-overexpressing (Retnla-Tg) mice. Retnla-Tg mice showed increased expression of Retnla protein in BAL fluid and airway epithelial cells. Retnla overexpression itself did not induce any alteration in lung histology or lung function compared to non-Tg controls. However, OVA-sensitized/challenged Retnla-Tg mice had decreased numbers of cells in BAL and inflammatory cells accumulating in the lung. They also showed a reduction in mucus production in the airway epithelium, concomitant with a decreased Muc5ac level. These results were accompanied by reduced levels of Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, with no effect on levels of OVA-specific immunoglobulin isotypes. Furthermore, phosphorylation of ERK was markedly reduced in the lungs of OVA-challenged Retnla-Tg mice. Taken together, these results indicates that Retnla protects against Th2-mediated inflammation in an experimental mouse model of asthma, suggesting that therapeutic approaches to enhance the production of Retnla or Retnla-like molecules could be valuable for preventing allergic lung inflammation.抵抗素样分子α（Resistin-like molecule alpha, Retnla）亦称“炎症区1蛋白（Found in inflammatory zone 1）”，是一种分泌型蛋白，已在卵清蛋白（ovalbumin, OVA）诱导的哮喘小鼠的支气管肺泡灌洗液（bronchoalveolar lavage, BAL）中被检出，可作为辅助性T细胞2（T helper, Th2）介导炎症的调控因子发挥作用。然而，Retnla在Th2介导的气道炎症进程中的具体作用尚未明确。为深入阐释Retnla在Th2介导气道炎症中的功能，我们构建了Retnla过表达（Retnla-overexpressing, Retnla-Tg）小鼠模型。该模型小鼠的支气管肺泡灌洗液及气道上皮细胞中，Retnla蛋白的表达水平显著升高。与非转基因（non-Tg）对照小鼠相比，单纯的Retnla过表达并未引发肺组织病理学或肺功能的异常改变。然而，经OVA致敏并攻击的Retnla-Tg小鼠，其支气管肺泡灌洗液中的细胞总数及肺部浸润的炎症细胞数量均有所减少；气道上皮的黏液分泌量也随之降低，同时伴随黏蛋白5AC（Muc5ac）表达水平的下调。上述表型与白细胞介素（interleukin, IL）-4、IL-5及IL-13等Th2型细胞因子的表达水平降低密切相关，而OVA特异性免疫球蛋白各亚型的水平未受影响。此外，经OVA攻击的Retnla-Tg小鼠肺部的细胞外调节蛋白激酶（extracellular signal-regulated kinase, ERK）磷酸化水平显著降低。综上，本研究结果表明，在哮喘实验小鼠模型中，Retnla可对Th2介导的肺部炎症起到保护作用，提示通过上调Retnla或类Retnla分子的表达以实施治疗干预，有望为过敏性肺部炎症的防治提供新的策略。