Linear ubiquitin assembly complex regulates lung epithelial-driven responses during influenza infection
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Author
Brazee, Patricia LMorales-Nebreda, Luisa
Magnani, Natalia D
Garcia, Joe G N
Misharin, Alexander V
Ridge, Karen M
Budinger, G R Scott
Iwai, Kazuhiro
Dada, Laura A
Sznajder, Jacob I
Affiliation
Univ Arizona, Dept MedIssue Date
2020-01-27
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AMER SOC CLINICAL INVESTIGATION INCCitation
Brazee, P. L., Morales-Nebreda, L., Magnani, N. D., Garcia, J. G., Misharin, A. V., Ridge, K. M., ... & Sznajder, J. I. (2020). Linear ubiquitin assembly complex regulates lung epithelial–driven responses during influenza infection. The Journal of Clinical Investigation, 130(3).Rights
© 2020, American Society for Clinical Investigation.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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-kappa B-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.ISSN
0022-0949EISSN
1558-8238PubMed ID
31714898Version
Final published versionae974a485f413a2113503eed53cd6c53
10.1172/JCI128368