Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Internal Medicine, Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
Viruses. 2021 Apr 16;13(4):692. doi: 10.3390/v13040692.
Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1β production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout () mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1β, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-β. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.
呼吸道合胞病毒 (RSV) 在两岁之前感染大多数婴儿。它会导致严重的疾病，增加日后患哮喘的风险。以前，我们的团队已经表明，RSV 感染在小鼠和婴儿中会促进 IL-1β 的产生。在这里，我们研究了 NLRP3 炎症小体在成年小鼠和新生儿 RSV 感染期间的激活作用。我们观察到，在体内 RSV 感染期间，使用小分子抑制剂 MCC950 或在基因改造的 NLRP3 敲除 () 小鼠中抑制 NLRP3 激活，可减少肺部免疫病理学，同时降低与严重 RSV 疾病相关的粘蛋白相关基因的表达，并减少先天细胞因子 (IL-1β、IL-33 和 CCL2) 的产生，而 IFN-β 的表达显著增加。NLRP3 炎症小体的抑制或缺失减少了 Th2 细胞因子和炎症细胞向肺部的浸润。此外，在 RSV 感染早期的生命阶段抑制或缺失 NLRP3 会导致在 RSV 诱导的过敏加重的小鼠模型中减少病毒加重的过敏反应。在这里，我们证明了 NLRP3 炎症小体在 RSV 免疫病理学和相关的长期气道改变中的关键作用。此外，这些发现表明 NLRP3 炎症小体是减轻严重 RSV 疾病和限制儿童哮喘发展的潜在治疗靶点。
