Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza

Interferon lambda (IFNλ) signaling is a promising therapeutic target against viral infection in murine models, yet little is known about its molecular regulation and its cognate receptor, interferon lambda receptor 1 (IFNLR1) in human lung. We hypothesized that the IFNλ signaling axis was active in...

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Autores principales:	Rama K. Mallampalli, Jessica Adair, Ajit Elhance, Daniela Farkas, Lexie Chafin, Matthew E. Long, Mithu De, Ana L. Mora, Mauricio Rojas, Victor Peters, Joseph S. Bednash, MuChun Tsai, James D. Londino
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	IFNLR1 interferon lambda influenza macrophage lung MCSF Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/c2a4910660b74ab6bd0cf80dde1bc0a3
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spelling	oai:doaj.org-article:c2a4910660b74ab6bd0cf80dde1bc0a32021-11-30T21:54:11ZInterferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza1664-322410.3389/fimmu.2021.735576https://doaj.org/article/c2a4910660b74ab6bd0cf80dde1bc0a32021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.735576/fullhttps://doaj.org/toc/1664-3224Interferon lambda (IFNλ) signaling is a promising therapeutic target against viral infection in murine models, yet little is known about its molecular regulation and its cognate receptor, interferon lambda receptor 1 (IFNLR1) in human lung. We hypothesized that the IFNλ signaling axis was active in human lung macrophages. In human alveolar macrophages (HAMs), we observed increased IFNLR1 expression and robust increase in interferon-stimulated gene (ISG) expression in response to IFNλ ligand. While human monocytes express minimal IFNLR1, differentiation of monocytes into macrophages with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) increased IFNLR1 mRNA, IFNLR1 protein expression, and cellular response to IFNλ ligation. Conversely, in mice, M-CSF or GM-CSF stimulated macrophages failed to produce ISGs in response to related ligands, IFNL2 or IFNL3, suggesting that IFNLR1 signaling in macrophages is species-specific. We next hypothesized that IFNλ signaling was critical in influenza antiviral responses. In primary human airway epithelial cells and precision-cut human lung slices, influenza infection substantially increased IFNλ levels. Pretreatment of both HAMs and differentiated human monocytes with IFNL1 significantly inhibited influenza infection. IFNLR1 knockout in the myeloid cell line, THP-1, exhibited reduced interferon responses to either direct or indirect exposure to influenza infection suggesting the indispensability of IFNLR1 for antiviral responses. These data demonstrate the presence of IFNλ - IFNLR1 signaling axis in human lung macrophages and a critical role of IFNλ signaling in combating influenza infection.Rama K. MallampalliJessica AdairAjit ElhanceDaniela FarkasLexie ChafinMatthew E. LongMatthew E. LongMithu DeAna L. MoraMauricio RojasVictor PetersJoseph S. BednashMuChun TsaiJames D. LondinoFrontiers Media S.A.articleIFNLR1interferon lambdainfluenzamacrophagelungMCSFImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	IFNLR1 interferon lambda influenza macrophage lung MCSF Immunologic diseases. Allergy RC581-607
spellingShingle	IFNLR1 interferon lambda influenza macrophage lung MCSF Immunologic diseases. Allergy RC581-607 Rama K. Mallampalli Jessica Adair Ajit Elhance Daniela Farkas Lexie Chafin Matthew E. Long Matthew E. Long Mithu De Ana L. Mora Mauricio Rojas Victor Peters Joseph S. Bednash MuChun Tsai James D. Londino Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
description	Interferon lambda (IFNλ) signaling is a promising therapeutic target against viral infection in murine models, yet little is known about its molecular regulation and its cognate receptor, interferon lambda receptor 1 (IFNLR1) in human lung. We hypothesized that the IFNλ signaling axis was active in human lung macrophages. In human alveolar macrophages (HAMs), we observed increased IFNLR1 expression and robust increase in interferon-stimulated gene (ISG) expression in response to IFNλ ligand. While human monocytes express minimal IFNLR1, differentiation of monocytes into macrophages with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) increased IFNLR1 mRNA, IFNLR1 protein expression, and cellular response to IFNλ ligation. Conversely, in mice, M-CSF or GM-CSF stimulated macrophages failed to produce ISGs in response to related ligands, IFNL2 or IFNL3, suggesting that IFNLR1 signaling in macrophages is species-specific. We next hypothesized that IFNλ signaling was critical in influenza antiviral responses. In primary human airway epithelial cells and precision-cut human lung slices, influenza infection substantially increased IFNλ levels. Pretreatment of both HAMs and differentiated human monocytes with IFNL1 significantly inhibited influenza infection. IFNLR1 knockout in the myeloid cell line, THP-1, exhibited reduced interferon responses to either direct or indirect exposure to influenza infection suggesting the indispensability of IFNLR1 for antiviral responses. These data demonstrate the presence of IFNλ - IFNLR1 signaling axis in human lung macrophages and a critical role of IFNλ signaling in combating influenza infection.
format	article
author	Rama K. Mallampalli Jessica Adair Ajit Elhance Daniela Farkas Lexie Chafin Matthew E. Long Matthew E. Long Mithu De Ana L. Mora Mauricio Rojas Victor Peters Joseph S. Bednash MuChun Tsai James D. Londino
author_facet	Rama K. Mallampalli Jessica Adair Ajit Elhance Daniela Farkas Lexie Chafin Matthew E. Long Matthew E. Long Mithu De Ana L. Mora Mauricio Rojas Victor Peters Joseph S. Bednash MuChun Tsai James D. Londino
author_sort	Rama K. Mallampalli
title	Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
title_short	Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
title_full	Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
title_fullStr	Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
title_full_unstemmed	Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
title_sort	interferon lambda signaling in macrophages is necessary for the antiviral response to influenza
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/c2a4910660b74ab6bd0cf80dde1bc0a3
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Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza

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