Macrophage Coordination of the Interferon Lambda Immune Response

Abstract

Lambda interferons (IFN-λs) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-λ not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-λ, uniquely positioned to bridge the gap between IFN-λ producing cells and lymphocyte populations that are not intrinsically responsive to IFN-λ. While CD14+ monocytes do not express the IFN-λ receptor, IFNLR1, sensitivity is quickly gained upon differentiation to macrophages in vitro. IFN-λ stimulates macrophage cytotoxicity and phagocytosis as well as the secretion of pro-inflammatory cytokines and interferon stimulated genes that mediate immune cell chemotaxis and effector functions. In particular, IFN-λ induced CCR5 and CXCR3 chemokines, stimulating T and NK cell migration, as well as subsequent NK cell cytotoxicity. Using immunofluorescence and cell sorting techniques, we confirmed that human liver macrophages expressing CD14 and CD68 are highly responsive to IFN-λ ex vivo. Together, these data highlight a novel role for macrophages in shaping IFN-λ dependent immune responses both directly through pro-inflammatory activity and indirectly by recruiting and activating IFN-λ unresponsive lymphocytes.

Monocytes differentiated into macrophages and dendritic cells in the presence of human IFN-λ3 or IFN-λ4 show distinct phenotypes

“…38 A very recent report suggested that IFN-3 could also have features of a Th1-like IFN, even though its evidences were based on IFN-3-treated MDMs. 12 In this report, Read et al described the immunomodulatory properties of IFN-3 on in vitro differentiated M1-and M2-MDMs, finding that IFN-3 could induce most of M1 markers but not M2 markers. Interestingly, they followed the same pretreatment strategy used herein ( Fig.…”

Interferon-Mediated Long Non-Coding RNA Response in Macrophages in the Context of HIV

“…To be able to fulfill all these functions, macrophages have a strong phenotypic plasticity [ 28 , 29 ], and, based on stimuli from their microenvironment, they can polarize into different types (classically activated M1 or alternatively activated M2 macrophages) [ 28 , 30 ]. Cytokines such as IFNs have an important role mediating the functional transition of macrophages throughout the innate immune response [ 31 ]. Wentker et al constructed a map of inflammation-related signal transduction pathways in macrophages, illustrating the overall dynamic coordination by transcriptional and post-transcriptional gene regulation [ 32 ] and Hu et al showed an extensive transcriptional response to the cytokine interleukin-27 in macrophages [ 14 ].…”

“…Read et al however demonstrated that macrophages are primary responders to IFN-λ, gaining IFN-λ receptor expression upon differentiation from CD14+ monocytes. Based on the induction of the interferon stimulated genes (ISGs) RSAD2/viperin and ISG15, they concluded that IFN-γ activates the transcription of ISGs [ 31 ]. However, we show here that, although there is measurable activation of ISGs as a result of IFN-λ stimulation, this effect is less pronounced than that observed for IFN Type I and II stimulation.…”

Interferon lambda 4 can directly activate human CD19+ B cells and CD8+ T cells

“…Although it is known that type I IFNs have anti-inflammatory properties because they inhibit IL-1β secretion (Huang et al, 1995;Billiau, 2006), little is known on the effects of type III IFN on IL-1β secretion. One study reported that IFNλ drives a pro-inflammatory phenotype during monocytes differentiation, increasing the secretion of inflammatory mediators including CCL2, IL-1β, and TNF (Read et al, 2019). IL-1β promotes inflammation by inducing the expression of proinflammatory genes, by recruiting immune cells to the site of The proportion of cells is differentially distributed across pseudotime in a lineage-dependent manner.…”