Type I interferon regulates proteolysis by macrophages to prevent immunopathology following viral infection.

Autor: Amanda J Lee, Emily Feng, Marianne V Chew, Elizabeth Balint, Sophie M Poznanski, Elizabeth Giles, Ali Zhang, Art Marzok, Spencer D Revill, Fatemeh Vahedi, Anisha Dubey, Ehab Ayaub, Rodrigo Jimenez-Saiz, Joshua J C McGrath, Tyrah M Ritchie, Manel Jordana, Danny D Jonigk, Maximilian Ackermann, Kjetil Ask, Matthew Miller, Carl D Richards, Ali A Ashkar
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: PLoS Pathogens, Vol 18, Iss 5, p e1010471 (2022)
Druh dokumentu: article
ISSN: 1553-7366
1553-7374
41243064
DOI: 10.1371/journal.ppat.1010471
Popis: The ability to treat severe viral infections is limited by our understanding of the mechanisms behind virus-induced immunopathology. While the role of type I interferons (IFNs) in early control of viral replication is clear, less is known about how IFNs can regulate the development of immunopathology and affect disease outcomes. Here, we report that absence of type I IFN receptor (IFNAR) is associated with extensive immunopathology following mucosal viral infection. This pathology occurred independent of viral load or type II immunity but required the presence of macrophages and IL-6. The depletion of macrophages and inhibition of IL-6 signaling significantly abrogated immunopathology. Tissue destruction was mediated by macrophage-derived matrix metalloproteinases (MMPs), as MMP inhibition by doxycycline and Ro 28-2653 reduced the severity of tissue pathology. Analysis of post-mortem COVID-19 patient lungs also displayed significant upregulation of the expression of MMPs and accumulation of macrophages. Overall, we demonstrate that IFNs inhibit macrophage-mediated MMP production to prevent virus-induced immunopathology and uncover MMPs as a therapeutic target towards viral infections.
Databáze: Directory of Open Access Journals
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