Linear ubiquitin assembly complex regulates lung epithelial-driven responses during influenza infection

J Clin Invest. 2020 Mar 2;130(3):1301-1314. doi: 10.1172/JCI128368.

Abstract

Influenza A virus (IAV) is among the most common causes of pneumonia-related death worldwide. Pulmonary epithelial cells are the primary target for viral infection and replication and respond by releasing inflammatory mediators that recruit immune cells to mount the host response. Severe lung injury and death during IAV infection result from an exuberant host inflammatory response. The linear ubiquitin assembly complex (LUBAC), composed of SHARPIN, HOIL-1L, and HOIP, is a critical regulator of NF-κB-dependent inflammation. Using mice with lung epithelial-specific deletions of HOIL-1L or HOIP in a model of IAV infection, we provided evidence that, while a reduction in the inflammatory response was beneficial, ablation of the LUBAC-dependent lung epithelial-driven response worsened lung injury and increased mortality. Moreover, we described a mechanism for the upregulation of HOIL-1L in infected and noninfected cells triggered by the activation of type I IFN receptor and mediated by IRF1, which was maladaptive and contributed to hyperinflammation. Thus, we propose that lung epithelial LUBAC acts as a molecular rheostat that could be selectively targeted to modulate the immune response in patients with severe IAV-induced pneumonia.

Keywords: Cellular immune response; Cytokines; Inflammation; Influenza; Pulmonology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Dogs
  • Humans
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / immunology
  • Lung / immunology*
  • Lung / pathology
  • Lung / virology
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / immunology*
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / pathology
  • Pneumonia, Viral / genetics
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / pathology
  • Respiratory Mucosa / immunology*
  • Respiratory Mucosa / pathology
  • Respiratory Mucosa / virology
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / immunology

Substances

  • Interferon Regulatory Factor-1
  • Irf1 protein, mouse
  • Multiprotein Complexes
  • Rbck1 protein, mouse
  • Rnf31 protein, mouse
  • Ubiquitin-Protein Ligases