Whitehead Gregory S, Karcz Tadeusz P, Tosh Dilip K, Jung Young-Hwan, Wen Zhiwei, Campbell Ryan G, Gopinatth Varun, Gao Zhan-Guo, Jacobson Kenneth A, Cook Donald N
Immunogenetics Group, Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, Durham, North Carolina 27709, United States.
Jagiellonian University Medical College, 30-688 Krakoẃ, Poland.
ACS Pharmacol Transl Sci. 2022 Oct 5;5(10):973-984. doi: 10.1021/acsptsci.2c00128. eCollection 2022 Oct 14.
COVID-19 disease is associated with progressive accumulation of SARS-CoV-2-specific mRNA, which is recognized by innate immune receptors, such as TLR3. This in turn leads to dysregulated production of multiple cytokines, including IL-6, IFN-γ, CXCL1, and TNF-α. Excessive production of these cytokines leads to acute lung injury (ALI), which consequently compromises alveolar exchange of O and CO. It is therefore of considerable interest to develop novel therapies that reduce pulmonary inflammation and stem production of pro-inflammatory cytokines, potentially for COVID-19 patients that are at high risk of developing severe disease. Purinergic signaling has a central role in fine-tuning the innate immune system, with P2 (nucleotide) receptor antagonists and adenosine receptor agonists having anti-inflammatory effects. Accordingly, we focused here on the potential role of purinergic receptors in driving neutrophilic inflammation and cytokine production in a mouse model of pulmonary inflammation. To mimic the effects of SARS-CoV-2-specific RNA accumulation in mice, we administered progressively increasing daily doses of a viral mimetic, polyinosinic:polycytidylic acid [poly(I:C)] into the airways of mice over the course of 1 week. Some mice also received increasing daily doses of ovalbumin to mimic virus-encoded protein accumulation. Animals receiving both poly(I:C) and ovalbumin displayed particularly high cytokine levels and neutrophilia, suggestive of both innate and antigen-specific, adaptive immune responses. The extent of these responses was diminished by genetic deletion (P2YR, P2X7R) or pharmacologic modulation (P2YR antagonists, AAR agonists) of purinergic receptors. These results suggest that pharmacologic modulation of select purinergic receptors might be therapeutically useful in treating COVID-19 and other pulmonary infections.
新冠肺炎与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）特异性mRNA的逐渐积累有关，该mRNA可被天然免疫受体（如Toll样受体3，TLR3）识别。这进而导致多种细胞因子（包括白细胞介素-6、干扰素-γ、CXC趋化因子配体1和肿瘤坏死因子-α）的产生失调。这些细胞因子的过度产生会导致急性肺损伤（ALI），从而损害肺泡对氧气和二氧化碳的交换。因此，开发新的疗法以减轻肺部炎症并阻止促炎细胞因子的产生，对于有发展为重症疾病高风险的新冠肺炎患者具有重要意义。嘌呤能信号在调节天然免疫系统中起核心作用，P2（核苷酸）受体拮抗剂和腺苷受体激动剂具有抗炎作用。因此，我们在此重点研究嘌呤能受体在小鼠肺部炎症模型中驱动中性粒细胞炎症和细胞因子产生方面的潜在作用。为模拟小鼠体内SARS-CoV-2特异性RNA积累的影响，我们在1周的时间内，每天向小鼠气道中递增剂量地给予一种病毒模拟物聚肌苷酸:聚胞苷酸[poly（I:C）]。一些小鼠还每天递增剂量地接受卵清蛋白以模拟病毒编码蛋白的积累。同时接受聚（I:C）和卵清蛋白的动物表现出特别高的细胞因子水平和中性粒细胞增多，提示存在天然免疫和抗原特异性适应性免疫反应。嘌呤能受体的基因缺失（P2Y受体、P2X7受体）或药理调节（P2Y受体拮抗剂、腺苷A受体激动剂）可减轻这些反应的程度。这些结果表明，对特定嘌呤能受体的药理调节可能对治疗新冠肺炎和其他肺部感染具有治疗作用。
