Type I interferon: friend or foe?

Abstract

Although the role of type I interferon (IFN) in the protection against viral infections has been known and studied for decades, its role in other immunologically relevant scenarios, including bacterial infections, shock, autoimmunity, and cancer, is less well defined and potentially much more complicated.

Figure 1.

Mechanisms of type I IFN production. Type I IFN production can be triggered by recognition of dsRNA by the cytosolic receptors MDA5 and RIG-I or of dsDNA (B-DNA) by DAI or as yet unknown cytosolic DNA receptors (DNA-RX), leading to activation of the IRF3 via the kinase TBK-1 (or IKKi) and culminating in production of type I IFN (IFNβ/α4). dsDNA can also be transcribed by RNA-polymerase III into 5′-pppRNA, which triggers RIG-I. The ability of the bacterial product cyclic-di-GMP to induce type I IFN suggests the existence of additional DNA sensors. The production of type I IFN can be amplified by a positive feedback loop in which the early produced IFN-β and IFN-α4 trigger the transcription of IRF7 and, at least in DCs, IRF8. In macrophages and DCs, ligation of TLR3, TLR4, TLR7, and TLR9 triggers type I IFN production via signaling through adaptor molecules, including MyD88, TIRAP, TRAM, and TRIF. TRIF associates with TBK1 to activate IRF3, whereas TLR7 and TLR9 signal through MyD88 and IRAK4 to activate IRF7. The cytoplasmic NOD receptors can also induce type I IFN production in response to bacterial cell wall components via activation of the kinase RICK and downstream signaling molecules including NF-κB and TBK-1.

Figure 2.

Effects of type I IFN on chemokine production and leukocyte recruitment. Type I IFN drives the production of chemokines, such as CCL2 and CCL7, which recruits CCR2-expressing TNF and inducible nitric oxide synthase–producing DCs (Tip-DCs) that are required for defense against Listeria infection. CCR2-expressing macrophages also contribute to lung pathology during influenza infection and are highly permissive to infection with M. tuberculosis. During influenza infection, type I IFN inhibits the production of the CXCR2 ligands CXCL1 and CXCL2, thus decreasing neutrophil recruitment and dampening host defense against secondary bacterial infections. However, type I IFN also drives the production of CXCL10, which recruits activated CXCR3-expressing neutrophils, thus protecting against sepsis in response to CLP.

Figure 3.

Cross-talk between type I IFN and IFN-γ. High levels of type I IFN (solid arrows) decrease the expression of IFNGR1 and inhibit IFN-γ-induced activation of MHC class II expression, oxidative burst, and bactericidal activity in macrophages. However, low constitutive levels of type I IFN (dashed arrows) prime cells for secondary responses to type I and II IFNs and IL-6 by favoring expression and activation of STAT1 (shown in fibroblasts). In DCs, low concentrations of type I IFN are essential for the optimal production of the IFN-γ–inducing cytokine IL-12p70, whereas higher levels of type I IFN suppress TLR- and IFN-γ–induced IL-12p40 expression, thus dampening IL-12p70 production. Type I IFN can also directly induce the production of IFN-γ in NK cell and T cells via the activation of STAT4.