Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States.
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States.
Am J Physiol Lung Cell Mol Physiol. 2024 Mar 1;326(3):L313-L329. doi: 10.1152/ajplung.00236.2023. Epub 2024 Jan 30.
Respiratory viral infections are one of the major causes of illness and death worldwide. Symptoms associated with respiratory infections can range from mild to severe, and there is limited understanding of why there is large variation in severity. Environmental exposures are a potential causative factor. The aryl hydrocarbon receptor (AHR) is an environment-sensing molecule expressed in all immune cells. Although there is considerable evidence that AHR signaling influences immune responses to other immune challenges, including respiratory pathogens, less is known about the impact of AHR signaling on immune responses during coronavirus (CoV) infection. In this study, we report that AHR activation significantly altered immune cells in the lungs and bone marrow of mice infected with a mouse CoV. AHR activation transiently reduced the frequency of multiple cells in the mononuclear phagocyte system, including monocytes, interstitial macrophages, and dendritic cells in the lung. In the bone marrow, AHR activation altered myelopoiesis, as evidenced by a reduction in granulocyte-monocyte progenitor cells and an increased frequency of myeloid-biased progenitor cells. Moreover, AHR activation significantly affected multiple stages of the megakaryocyte lineage. Overall, these findings indicate that AHR activation modulates multiple aspects of the immune response to a CoV infection. Given the significant burden of respiratory viruses on human health, understanding how environmental exposures shape immune responses to infection advances our knowledge of factors that contribute to variability in disease severity and provides insight into novel approaches to prevent or treat disease. Our study reveals a multifaceted role for aryl hydrocarbon receptor (AHR) signaling in the immune response to coronavirus (CoV) infection. Sustained AHR activation during in vivo mouse CoV infection altered the frequency of mature immune cells in the lung and modulated emergency hematopoiesis, specifically myelopoiesis and megakaryopoiesis, in bone marrow. This provides new insight into immunoregulation by the AHR and extends our understanding of how environmental exposures can impact host responses to respiratory viral infections.
呼吸道病毒感染是全球范围内导致疾病和死亡的主要原因之一。与呼吸道感染相关的症状可从轻微到严重不等，而对于为什么严重程度存在很大差异，人们的了解有限。环境暴露是一个潜在的致病因素。芳香烃受体（AHR）是一种存在于所有免疫细胞中的环境感应分子。尽管有大量证据表明 AHR 信号会影响对其他免疫挑战（包括呼吸道病原体）的免疫反应，但对于 AHR 信号对冠状病毒（CoV）感染期间免疫反应的影响知之甚少。在这项研究中，我们报告说 AHR 激活显着改变了感染小鼠 CoV 的肺部和骨髓中的免疫细胞。AHR 激活会短暂降低单核吞噬细胞系统中多种细胞的频率，包括肺部的单核细胞、间质巨噬细胞和树突状细胞。在骨髓中，AHR 激活改变了骨髓生成，表现为粒细胞-单核细胞祖细胞减少和偏骨髓祖细胞频率增加。此外，AHR 激活显着影响巨核细胞谱系的多个阶段。总的来说，这些发现表明 AHR 激活调节了对 CoV 感染的免疫反应的多个方面。鉴于呼吸道病毒对人类健康的巨大负担，了解环境暴露如何塑造对感染的免疫反应，增进了我们对导致疾病严重程度差异的因素的认识，并为预防或治疗疾病提供了新的思路。我们的研究揭示了 AHR 信号在冠状病毒（CoV）感染免疫反应中的多方面作用。在体内感染小鼠 CoV 期间持续激活 AHR 改变了肺部成熟免疫细胞的频率，并调节了骨髓中的紧急造血，特别是骨髓生成和巨核细胞生成。这为 AHR 的免疫调节提供了新的见解，并扩展了我们对环境暴露如何影响宿主对呼吸道病毒感染的反应的理解。
