tetano
Editor, Senior Moderator
Front Immunol
. 2021 Nov 25;12:735576.
doi: 10.3389/fimmu.2021.735576. eCollection 2021.
Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
Rama K Mallampalli[SUP] 1 [/SUP], Jessica Adair[SUP] 1 [/SUP], Ajit Elhance[SUP] 1 [/SUP], Daniela Farkas[SUP] 1 [/SUP], Lexie Chafin[SUP] 1 [/SUP], Matthew E Long[SUP] 1 2 [/SUP], Mithu De[SUP] 1 [/SUP], Ana L Mora[SUP] 1 [/SUP], Mauricio Rojas[SUP] 1 [/SUP], Victor Peters[SUP] 1 [/SUP], Joseph S Bednash[SUP] 1 [/SUP], MuChun Tsai[SUP] 1 [/SUP], James D Londino[SUP] 1 [/SUP]
Affiliations
Abstract
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.
Keywords: GMCSF; IFNLR1; MCSF; influenza; interferon lambda; lung; macrophage.
. 2021 Nov 25;12:735576.
doi: 10.3389/fimmu.2021.735576. eCollection 2021.
Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
Rama K Mallampalli[SUP] 1 [/SUP], Jessica Adair[SUP] 1 [/SUP], Ajit Elhance[SUP] 1 [/SUP], Daniela Farkas[SUP] 1 [/SUP], Lexie Chafin[SUP] 1 [/SUP], Matthew E Long[SUP] 1 2 [/SUP], Mithu De[SUP] 1 [/SUP], Ana L Mora[SUP] 1 [/SUP], Mauricio Rojas[SUP] 1 [/SUP], Victor Peters[SUP] 1 [/SUP], Joseph S Bednash[SUP] 1 [/SUP], MuChun Tsai[SUP] 1 [/SUP], James D Londino[SUP] 1 [/SUP]
Affiliations
- PMID: 34899695
- PMCID: PMC8655102
- DOI: 10.3389/fimmu.2021.735576
Abstract
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.
Keywords: GMCSF; IFNLR1; MCSF; influenza; interferon lambda; lung; macrophage.