Interferon-lambda is a key player in defending the human lungs against influenza by activating macrophages and suppressing viral infection, as demonstrated by researchers from the Davis Heart and Lung Research Institute in the United States.
IFN-λ is the most prevalent and earliest interferon during influenza infection. Influenza triggers an immune response through the innate immune system: viral RNA activates the proteins RIG-I and MAVS, producing type I (IFN-α, IFN-β) and type III (IFN-λ) interferons. IFN-λ has a unique property—it suppresses inflammation, whereas IFN-α, in contrast, enhances inflammatory processes.
Studies in mice have shown that IFN-λ is critically essential for protection against influenza: the absence of an IFN-λ response leads to severe disease and death, whereas IFN-λ administration reduces inflammation and viral load. In cellular models and human lung tissue, IFN-λ is produced earlier and in more significant quantities than type I interferons.
The present study found that IFN-λ exhibits the highest expression among interferons in the human respiratory epithelium. They also discovered that the IFN-λ receptor (IFNLR1) is most strongly expressed in alveolar macrophages in human lungs. These macrophages respond to IFN-λ by activating interferon-stimulated genes (ISG).
Influenza Infection Triggers an IFN-λ1 Response in the Respiratory Tract
Researchers infected human respiratory epithelial cells with the influenza virus. Within 24-48 hours, IFN-β, IFN-λ1, and IFN-λ2/3 were actively produced, with IFN-λ1 and IFN-λ2/3 showing the highest expression levels.
When human lung slices were infected with influenza virus, the cells produced high levels of IFN-γ, followed by IFN-λ1 and IFN-α2, while IFN-β levels remained nearly unchanged.
Alveolar Macrophages Express the IFN-λ Receptor
Since IFN-λ was actively produced in influenza-infected lungs, researchers investigated where its receptor IFNLR1 was expressed. Analysis revealed that IFNLR1 expression was highest in alveolar macrophages, with lower levels in epithelial cells. Notably, IFNLR1 was expressed only in differentiated macrophages and was absent in undifferentiated CD14 monocytes, confirming that IFNLR1 expression is linked to macrophage differentiation.
Monocyte Differentiation into Macrophages Increases IFNLR1 Expression and Function
Researchers examined how IFNLR1 expression is regulated in macrophages and how they respond to interferons:
- Alveolar macrophages respond to IFN-λ1. In response to IFN-λ1, alveolar macrophages activate ISG at the same level as IFN-β, except for ISG15, which responds more strongly to IFN-λ
- Macrophage differentiation increases IFNLR1 expression. Monocytes exhibit minimal IFNLR1 expression, but differentiation into macrophages using macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) markedly increases IFNLR1 levels. Macrophages differentiated with GM-CSF show a more sustained response to IFN-λ1 than those with M-CSF.
- IFN-λ1 and IFN-β induce similar ISG activation. Following GM-CSF macrophage treatment, both interferons activated ISG equally. IFN-λ3 had a similar effect on ISG activation at the same concentration.
- Influenza does not alter IFNLR1 levels in macrophages. When researchers infected GM-CSF macrophages with flu, the infection did not change IFNLR1 mRNA levels.
- Mouse macrophages do not respond to IFN-λ. IFNLR1 expression in mouse macrophages remained unchanged upon interferon stimulation. Unlike human macrophages, mouse macrophages respond well to IFN-β but show minimal response to IFN-λ.
Influenza Infection of Macrophages Leads to IFN-λ Production
Macrophages differentiated with M-CSF and GM-CSF responded to influenza infection. GM-CSF macrophages exhibited a weaker immune response to influenza. Infection led to sustained increases in IL-6 and TNFα, while levels of other cytokines remained unchanged.
Following influenza infection, macrophages actively produced type I and type III interferons. Unlike respiratory epithelial cells, macrophages exhibited a substantial increase in IFN-α. The primary secreted interferon in both macrophage types was IFN-λ1.
IFN-λ Suppresses Macrophage Infection
Researchers pre-treated macrophages with IFN-λ1 one day before influenza infection. IFN-λ1 suppressed infection and reduced levels of inflammatory cytokines TNFα, MIP1α, and MIP1β, which are responsible for the inflammatory response to influenza. Compared to IFN-β, IFN-λ1 was less potent but still inhibited the virus. Given its antiviral activity and high lung circulating levels, IFNLR1 likely plays a key role in suppressing macrophage infection.
IFNLR1 is Essential for ISG Expression
Researchers examined how macrophages lacking the IFN-λ receptor responded to influenza. ISG activation was weaker after infection, and viral mRNA levels were higher. In IFNLR1-deficient cells, inflammatory cytokines IL1-β, TNF-α, IL-6, and MIP1-α were elevated. However, the secretion of MIP1-β and MCP-1 was reduced, as their production depends on IFN signaling.
Alveolar macrophages become infected and respond to interferons produced by respiratory epithelial cells. Researchers treated IFNLR1-deficient macrophages with conditioned medium from influenza-infected epithelial cells. While this medium activated ISG in normal cells, the response was significantly weakened in IFNLR1-deficient cells. Thus, IFNLR1, through its interaction with IFN-λ, is necessary for protection against influenza.
Conclusion
Unlike type I interferons (IFN-α, IFN-β), IFN-λ suppresses viral replication without inducing intense inflammation, making it a promising candidate for influenza and other viral infections. However, its role in humans remains insufficiently studied, and macrophage responses to IFN-λ may be species-dependent.
IFN-λ is produced earlier and more significantly during influenza infection than type I interferons. The IFNLR1 receptor is highly expressed in human alveolar macrophages, enabling these cells to respond to IFN-λ and protect against influenza.
The most active interferon in lung tissue is IFN-γ, produced by NK cells and CD8+ T cells in response to influenza. In macrophages, IFN-λ is strongly activated during infection. Depleting macrophages before influenza infection increases viral load and mortality in mice and pigs. Certain influenza strains, such as H5N1, exhibit greater infectivity in macrophages.
IFN-λ reduces inflammation and viral load. Macrophages with IFNLR1 respond to circulating IFN-λ and suppress viral infection. Without IFNLR1, inflammatory cytokine production (TNFα, IL-1β, IL-6) increases, while chemokine levels (CCL2, CCL4) decrease. IFNLR1 enables macrophages to respond to signals from infected respiratory epithelial cells and initiate an antiviral response. Without IFNLR1, the immune response is weakened. IFN-λ plays a crucial role in lung protection against influenza.
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Reference
Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
