Linear ubiquitin assembly complex regulates lung epithelial–driven responses during influenza infection
Patricia L. Brazee, Luisa Morales-Nebreda, Natalia D. Magnani, Joe G.N. Garcia, Alexander V. Misharin, Karen M. Ridge, G.R. Scott Budinger, Kazuhiro Iwai, Laura A. Dada, Jacob I. Sznajder
Patricia L. Brazee, Luisa Morales-Nebreda, Natalia D. Magnani, Joe G.N. Garcia, Alexander V. Misharin, Karen M. Ridge, G.R. Scott Budinger, Kazuhiro Iwai, Laura A. Dada, Jacob I. Sznajder
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Research Article Inflammation Pulmonology

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

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.

Authors

Patricia L. Brazee, Luisa Morales-Nebreda, Natalia D. Magnani, Joe G.N. Garcia, Alexander V. Misharin, Karen M. Ridge, G.R. Scott Budinger, Kazuhiro Iwai, Laura A. Dada, Jacob I. Sznajder

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Figure 8

Illustration representing HOIL-1L upregulation via IRF1 in AT2 cells.

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Illustration representing HOIL-1L upregulation via IRF1 in AT2 cells. Up...
Upon IAV infection, LUBAC-dependent activation of NF-κB and IRF3 pathways occurs downstream of RIG-I. Subsequent release of proinflammatory cytokines and type I IFNs recruits immune cells to the airspace, contributing to the growing cytokine storm. In noninfected AT2 cells, IFN secreted by either epithelial cells or the recruited immune cells binds to IFNAR1, triggering a signal cascade that upregulates HOIL-1L via IRF1. Newly synthesized HOIL-1L may contribute to either an increased number of LUBAC complexes or a change in LUBAC stoichiometry to include a higher ratio of HOIL-1L within the complex. Both situations result in increased stability of LUBAC and exaggerated production of cytokines, which contributes to the morbidity and mortality observed in severe cases of influenza infection.