Chang Lu1, Xuemei Zhang1, Chenyu Ma2, Wenchun Xu1, Lingling Gan1, Jin Cui3, Yibing Yin1, Hong Wang4. 1. Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, 400016 Chongqing, China; School of Laboratory Medicine, Chongqing Medical University, 400016 Chongqing, China. 2. Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, 400016 Chongqing, China; School of Laboratory Medicine, Chongqing Medical University, 400016 Chongqing, China; Department of Laboratory Diagnosis, The Central Hospital of Xianyang, 712000, Shaanxi, China. 3. Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, 400016 Chongqing, China; The Center for Clinical Molecular Medical Detection, The first Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China. 4. Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, 400016 Chongqing, China; School of Laboratory Medicine, Chongqing Medical University, 400016 Chongqing, China. Electronic address: wanghongljf@cqmu.edu.cn.
Abstract
Nontypeable Haemophilus influenzae (NTHI) is one of the leading causes of acute exacerbations of COPD (AECOPD). Although the immunoregulation function of NTHI outer member protein and endotoxin were confirmed, the role of NTHI DNA in activating immune responses remains to be elucidated. In this study, we found expression of IFN-β and IFN stimulated gene CXCL10 in host cells was forcefully elevated after treating with NTHI and NTHI DNA. Interestingly, we tested increased level of STING in NTHI infected mice lung. Meanwhile, STING expression in lung of mimic COPD murine model was higher than healthy mice after NTHI infection. Importantly, knockout of STING or overexpression of STING, TBK1 and IRF3 respectively impaired or enhanced IFN-β and CXCL10 expression during treating with NTHI and NTHI DNA. NTHI and NTHI DNA-induced I-IFN response appeared to be mediated by cGAS. Collectively, we suggested that NTHI DNA as a PAMP triggered I-IFN response, which was STING/TBK1/IRF3 dependent. SUMMARY: NTHI is the leading cause of acute exacerbations of COPD (AECOPD). Since AECOPD is an immune event, it is meaningful to elucidate the mechanism under NTHI induced immune response. It has been revealed that lipooligosaccharides and protein of NTHI could induce host immune response, but the function of NTHI nuclide acid during infection is unclear. In this research, we demonstrate NTHI DNA is a trigger for I-IFN expression, and the STING/TBK1/IRF3 pathway plays an integral role in sensing NTHI DNA to induce I-IFN expression. Moreover, by long-term intrabronchial infection of LPS, we constructed a mimic COPD murine model, in which the STING expression in lung tissues were higher than healthy mice after NTHI infection, which led us to surmise that NTHI cause AECOPD by inducing I-IFN production via STING signal pathway.
Nontypeable Haemophilus influenzae (NTHI) is one of the leading causes of acute exacerbations of COPD (AECOPD). Although the immunoregulation function of NTHI outer member protein and endotoxin were confirmed, the role of NTHI DNA in activating immune responses remains to be elucidated. In this study, we found expression of IFN-β and IFN stimulated gene CXCL10 in host cells was forcefully elevated after treating with NTHI and NTHI DNA. Interestingly, we tested increased level of STING in NTHI infected mice lung. Meanwhile, STING expression in lung of mimic COPDmurine model was higher than healthy mice after NTHIinfection. Importantly, knockout of STING or overexpression of STING, TBK1 and IRF3 respectively impaired or enhanced IFN-β and CXCL10 expression during treating with NTHI and NTHI DNA. NTHI and NTHI DNA-induced I-IFN response appeared to be mediated by cGAS. Collectively, we suggested that NTHI DNA as a PAMP triggered I-IFN response, which was STING/TBK1/IRF3 dependent. SUMMARY:NTHI is the leading cause of acute exacerbations of COPD (AECOPD). Since AECOPD is an immune event, it is meaningful to elucidate the mechanism under NTHI induced immune response. It has been revealed that lipooligosaccharides and protein of NTHI could induce host immune response, but the function of NTHI nuclide acid during infection is unclear. In this research, we demonstrate NTHI DNA is a trigger for I-IFN expression, and the STING/TBK1/IRF3 pathway plays an integral role in sensing NTHI DNA to induce I-IFN expression. Moreover, by long-term intrabronchial infection of LPS, we constructed a mimic COPDmurine model, in which the STING expression in lung tissues were higher than healthy mice after NTHIinfection, which led us to surmise that NTHI cause AECOPD by inducing I-IFN production via STING signal pathway.