To elucidate the involvement of intracellular DNA recognition mechanism in the pathogenesis of COPD

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08510
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Tohoku University
• Principal Investigator: Koarai Akira 東北大学, 大学病院, 講師 (80458059)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 自然免疫応答 / 酸化ストレス / 慢性閉塞性肺疾患 / DNA

Outline of Final Research Achievements

It is suggested that abnormal innate immune responses may play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and its exacerbations. In this study, we demonstrated for the first time that oxidative stress such as cigarette smoke suppresses IFN-β production in airway epithelial and macrophage cells via the cGAS-STING pathway, a novel intracytoplasmic DNA recognition mechanism. However, in the presence of chronic airway inflammation in airway epithelial cells derived from COPD patients, DNA-stimulated IFN-β production was enhanced, indicating a difference in responsiveness between COPD patients and healthy controls. In the future, clarification of the differences in innate immune responses to DNA stimulation between healthy and COPD-derived cells may lead to a better understanding of the pathogenesis of COPD exacerbations.

Free Research Field

閉塞性肺疾患

Academic Significance and Societal Importance of the Research Achievements

今回、気道上皮やマクロファージ細胞においてタバコ煙などの酸化ストレスが新規細胞質内DNA認識機構であるcGAS-STING経路を介したIFN-β産生を抑制する機構が存在することを初めて示した。しかしながら、COPD患者由来の気道上皮細胞における慢性気道炎症病態の存在下ではdsDNA刺激によるIFN-β産生が亢進しており、健常者との反応性の違いが明らかとなった。今後、健常者とCOPD由来の細胞でのDNA刺激に対する自然免疫応答の違いを明らかにすることによりCOPD増悪病態の解明につながる可能性がある。