title: TGF-β-induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice.
abstract: As the eighth leading cause of annual mortality in the USA, influenza A viruses are a major public health concern. In 20% of patients, severe influenza progresses to acute lung injury (ALI). However, pathophysiological mechanisms underlying ALI development are poorly defined. We reported that, unlike wild-type (WT) C57BL/6 controls, influenza A virus-infected mice that are heterozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (HETs) did not develop ALI. This effect was associated with higher IL-6 and alveolar macrophages (AMs) at 6 days postinfection (d.p.i.) in HET bronchoalveolar lavage fluid (BALF). In the present study, we found that HET AMs were an important source of IL-6 at 6 d.p.i. Infection also induced TGF-β production by HET but not WT mice at 2 d.p.i. TGF-β neutralization at 2 d.p.i. (TGF-N) significantly reduced BALF IL-6 in HETs at 6 d.p.i. Neither TGF-N nor IL-6 neutralization at 4 d.p.i. (IL-6-N) altered postinfection weight loss or viral replication in either mouse strain. However, both treatments increased influenza A virus-induced hypoxemia, pulmonary edema, and lung dysfunction in HETs to WT levels at 6 d.p.i. TGF-N and IL-6-N did not affect BALF AM and neutrophil numbers but attenuated the CXCL-1/keratinocyte chemokine response in both strains and reduced IFN-γ production in WT mice. Finally, bone marrow transfer experiments showed that HET stromal and myeloid cells are both required for protection from ALI in HETs. These findings indicate that TGF-β-dependent production of IL-6 by AMs later in infection prevents ALI development in influenza A virus-infected HET mice.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio;
authors.forename: Parker S
authors.initials: PS
authors.lastname: Woods
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio.
authors.forename: Mia F
authors.initials: MF
authors.lastname: Tazi
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Chesarino
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio.
authors.forename: Amal O
authors.initials: AO
authors.lastname: Amer
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio; davis.2448@osu.edu.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Davis
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000821:virology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D007113:Immunity, Innate; D009980:Influenza A virus / Q000276:immunology*; D015850:Interleukin-6 / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000821:virology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D017384:Sequence Deletion; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: acute lung injury; cystic fibrosis transmembrane conductance regulator; influenza; interleukin-6; transforming growth factor-β
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