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

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.

Antiviral activity of adenoviral vector expressing human interferon lambda‐4 against influenza virus

“…In humans, the IFNλ‐IFNLR1 signaling axis is crucial in inhibiting influenza infection 24,25 . While there is currently no clinically approved IFNλ drug, clinical trial results demonstrate its efficacy in reducing the pathogenesis or viral load caused by respiratory infections, including COVID‐19 26,27 .…”

Ly6C+ monocytes in the skin promote systemic alphavirus dissemination

“… 43 Alternatively, monocytes may not respond to the dominant IFN (type III, IFN-λ) at epithelial barrier surfaces 44 – 46 because they lack expression of the IFNLR1 subunit. 47 – 49 Differences in permissiveness to CHIKV infection of monocytes from blood, DLN, and tissue also could be due to their transcriptional or programmatic differences. 50 It will be important to continue to characterize monocyte subsets and their functions in diverse inflammatory settings, including during virus infections such as CHIKV.…”

The E3 ligase subunit FBXO45 binds the interferon-λ receptor and promotes its degradation during influenza virus infection

“…Studies have shown that early IFN-λ treatment in mice during influenza virus infection offers significant antiviral protection without the proinflammatory responses associated with Type 1 interferons ( 6 , 25 ). Although we have previously demonstrated the presence of the IFN-λ–IFNLR1 signaling axis in human lung macrophages and its role in combating influenza infection, the expression, signaling, and molecular regulation of IFNLR1 in human bronchial epithelial cells has not been fully elucidated ( 26 ).…”