RIG-I agonist SLR10 promotes macrophage M1 polarization during influenza virus infection

Frontiers in Immunology

Immunology

Chao Xu¹  Craig A. Miller²  Wenxin Wu³  Wei Zhang³  Jeremy S. Alexandar³  J. Leland Booth³  Jordan P. Metcalf⁴ 

[1] Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States;Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Oklahoma State University, Stillwater, OK, United States;Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States;Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States;Pulmonary Section, Medicine Service, Veterans Affairs Medical Center, Oklahoma City, OK, United States;Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States;

关键词: influenza virus;    RIG-I;    agonist;    SLR10;    smoking;    innate immunity;    macrophage polarization;   

DOI  :  10.3389/fimmu.2023.1177624

 received in 2023-03-01, accepted in 2023-06-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

RationaleA family of short synthetic, triphosphorylated stem-loop RNAs (SLRs) have been designed to activate the retinoic-acid-inducible gene I (RIG-I) pathway and induce a potent interferon (IFN) response, which may have therapeutic potential. We investigated immune response modulation by SLR10. We addressed whether RIG-I pathway activation with SLR10 leads to protection of nonsmoking (NS) and cigarette smoke (CS)-exposed mice after influenza A virus (IAV) infection.MethodsMice were given 25 µg of SLR10 1 day before IAV infection. We compared the survival rates and host immune responses of NS and CS-exposed mice following challenge with IAV.ResultsSLR10 significantly decreased weight loss and increased survival rates in both NS and CS-exposed mice during IAV infection. SLR10 administration repaired the impaired proinflammatory response in CS-exposed mice without causing more lung injury in NS mice as assessed by physiologic measurements. Although histopathologic study revealed that SLR10 administration was likely to result in higher pathological scores than untreated groups in both NS and CS mice, this change was not enough to increase lung injury evaluated by lung-to-body weight ratio. Both qRT-PCR on lung tissues and multiplex immunoassay on bronchoalveolar lavage fluids (BALFs) showed that most IFNs and proinflammatory cytokines were expressed at lower levels in SLR10-treated NS mice than control-treaded NS mice at day 5 post infection (p.i.). Remarkably, proinflammatory cytokines IL-6, IL-12, and GM-CSF were increased in CS-exposed mice by SLR10 at day 5 p.i. Significantly, SLR10 elevated the ratio of the two chemokines (CXCL9 and CCL17) in BALFs, suggesting macrophages were polarized to classically activated (M1) status. In vitro testing also found that SLR10 not only stimulated human alveolar macrophage polarization to an M1 phenotype, but also reversed cigarette smoke extract (CSE)-induced M2 to M1 polarization.ConclusionsOur data show that SLR10 administration in mice is protective for both NS and CS-exposed IAV-infected mice. Mechanistically, SLR10 treatment promoted M1 macrophage polarization in the lung during influenza infection. The protective effects by SLR10 may be a promising intervention for therapy for infections with viruses, particularly those with CS-enhanced susceptibility to adverse outcomes.

【 授权许可】

Unknown   
Copyright © 2023 Wu, Zhang, Alexandar, Booth, Miller, Xu and Metcalf