Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL; and.
Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
J Immunol. 2022 May 15;208(10):2390-2402. doi: 10.4049/jimmunol.2101085. Epub 2022 Apr 22.
Respiratory viruses stimulate the release of antiviral IFNs from the airway epithelium. Previous studies have shown that asthmatic patients show diminished release of type I and type III IFNs from bronchial epithelia. However, the mechanism of this suppression is not understood. In this study, we report that extracellular nucleotides and histamine, which are elevated in asthmatic airways, strongly inhibit release of type I and type III IFNs from human bronchial airway epithelial cells (AECs). Specifically, ATP, UTP, and histamine all inhibited the release of type I and type III IFNs from AECs induced by activation of TLR3, retinoic acid-inducible gene I (RIG-I), or cyclic GMP-AMP synthase-STING. This inhibition was at least partly mediated by Gq signaling through purinergic P2Y and H receptors, but it did not involve store-operated calcium entry. Pharmacological blockade of protein kinase C partially reversed inhibition of IFN production. Conversely, direct activation of protein kinase C with phorbol esters strongly inhibited TLR3- and RIG-I-mediated IFN production. Inhibition of type I and type III IFNs by ATP, UTP, histamine, and the proteinase-activated receptor 2 (PAR2) receptor agonist SLIGKV also occurred in differentiated AECs grown at an air-liquid interface, indicating that the suppression is conserved following mucociliary differentiation. Importantly, histamine and, more strikingly, ATP inhibited type I IFN release from human airway cells infected with live influenza A virus or rhinovirus 1B. These results reveal an important role for extracellular nucleotides and histamine in attenuating the induction of type I and III IFNs from AECs and help explain the molecular basis of the suppression of IFN responses in asthmatic patients.
呼吸道病毒刺激气道上皮细胞释放抗病毒干扰素。先前的研究表明，哮喘患者支气管上皮细胞释放的 I 型和 III 型干扰素减少。然而，这种抑制的机制尚不清楚。在这项研究中，我们报告说，在哮喘气道中升高的细胞外核苷酸和组氨酸强烈抑制人支气管气道上皮细胞 (AEC) 释放 I 型和 III 型干扰素。具体而言，ATP、UTP 和组氨酸均抑制 TLR3、视黄酸诱导基因 I (RIG-I) 或环鸟苷酸-AMP 合酶-STING 激活诱导的 AEC 中 I 型和 III 型干扰素的释放。这种抑制至少部分是通过嘌呤能 P2Y 和 H 受体通过 Gq 信号传导介导的，但它不涉及储存操作的钙进入。蛋白激酶 C 的药理学阻断部分逆转了 IFN 产生的抑制。相反，佛波酯对蛋白激酶 C 的直接激活强烈抑制 TLR3 和 RIG-I 介导的 IFN 产生。ATP、UTP、组氨酸和蛋白酶激活受体 2 (PAR2) 受体激动剂 SLIGKV 对 I 型和 III 型干扰素的抑制也发生在在气液界面培养的分化 AEC 中，表明在纤毛分化后抑制作用得以保留。重要的是，组氨酸，更显著的是 ATP，抑制了感染活流感 A 病毒或鼻病毒 1B 的人气道细胞中 I 型 IFN 的释放。这些结果揭示了细胞外核苷酸和组氨酸在减弱 AEC 中 I 型和 III 型干扰素诱导中的重要作用，并有助于解释哮喘患者 IFN 反应抑制的分子基础。
