Shikotra Aarti, Choy David F, Siddiqui Salman, Arthur Greer, Nagarkar Deepti R, Jia Guiquan, Wright Adam K A, Ohri Chandra M, Doran Emma, Butler Claire A, Hargadon Beverley, Abbas Alexander R, Jackman Janet, Wu Lawren C, Heaney Liam G, Arron Joseph R, Bradding Peter
Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester LE3 9QP, United Kingdom.
Genentech, Inc., South San Francisco, CA 94080.
J Immunol. 2017 Apr 15;198(8):3307-3317. doi: 10.4049/jimmunol.1600606. Epub 2017 Mar 8.
Severe asthma represents a major unmet clinical need; understanding the pathophysiology is essential for the development of new therapies. Using microarray analysis, we previously found three immunological clusters in asthma: Th2-high, Th17-high, and Th2/17-low. Although new therapies are emerging for Th2-high disease, identifying molecular pathways in Th2-low disease remains an important goal. Further interrogation of our previously described microarray dataset revealed upregulation of gene expression for carcinoembryonic Ag cell adhesion molecule (CEACAM) family members in the bronchi of patients with severe asthma. Our aim was therefore to explore the distribution and cellular localization of CEACAM6 using immunohistochemistry on bronchial biopsy tissue obtained from patients with mild-to-severe asthma and healthy control subjects. Human bronchial epithelial cells were used to investigate cytokine and corticosteroid in vitro regulation of CEACAM6 gene expression. CEACAM6 protein expression in bronchial biopsies was increased in airway epithelial cells and lamina propria inflammatory cells in severe asthma compared with healthy control subjects. CEACAM6 in the lamina propria was localized to neutrophils predominantly. Neutrophil density in the bronchial mucosa was similar across health and the spectrum of asthma severity, but the percentage of neutrophils expressing CEACAM6 was significantly increased in severe asthma, suggesting the presence of an altered neutrophil phenotype. CEACAM6 gene expression in cultured epithelial cells was upregulated by wounding and neutrophil elastase. In summary, CEACAM6 expression is increased in severe asthma and primarily associated with airway epithelial cells and tissue neutrophils. CEACAM6 may contribute to the pathology of treatment-resistant asthma via neutrophil and airway epithelial cell-dependent pathways.
重度哮喘是一个尚未满足的重大临床需求；了解其病理生理学对于开发新疗法至关重要。通过微阵列分析，我们先前在哮喘中发现了三个免疫集群：Th2高、Th17高和Th2/17低。尽管针对Th2高疾病的新疗法不断涌现，但确定Th2低疾病中的分子途径仍然是一个重要目标。对我们先前描述的微阵列数据集的进一步研究发现，重度哮喘患者支气管中癌胚抗原细胞粘附分子（CEACAM）家族成员的基因表达上调。因此，我们的目的是使用免疫组织化学方法，对从轻度至重度哮喘患者和健康对照受试者获取的支气管活检组织进行研究，以探索CEACAM6的分布和细胞定位。使用人支气管上皮细胞在体外研究细胞因子和皮质类固醇对CEACAM6基因表达的调节。与健康对照受试者相比，重度哮喘患者支气管活检中的CEACAM6蛋白表达在气道上皮细胞和固有层炎症细胞中增加。固有层中的CEACAM6主要定位于中性粒细胞。在健康状态和哮喘严重程度范围内，支气管黏膜中的中性粒细胞密度相似，但在重度哮喘中表达CEACAM6的中性粒细胞百分比显著增加，提示存在改变的中性粒细胞表型。培养的上皮细胞中CEACAM6基因表达受到创伤和中性粒细胞弹性蛋白酶的上调。总之，CEACAM6表达在重度哮喘中增加，并且主要与气道上皮细胞和组织中性粒细胞相关。CEACAM6可能通过中性粒细胞和气道上皮细胞依赖性途径促成难治性哮喘的病理过程。
