Immunomodulatory functions of type I interferons

Abstract

Interferon-α (IFNα) and IFNβ, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases.

Figure 1. Signalling pathways activated by type I and type II IFNs

Different signal transducer and activator of transcription (STAT) family members can be activated by interferons (IFNs). STAT1 homodimers can be formed in response to both type I IFNs and type II IFN (IFNγ). These homodimers bind to IFNγ-activated site (GAS) enhancer elements in the promoters of IFN-stimulated genes, and this results in the induction of genes encoding pro-inflammatory cytokines and apoptotic factors. Type I and type II IFNs can also activate STAT3 homodimers, and this can result in the production of both pro-inflammatory cytokines and anti-inflammatory cytokines (such as interleukin-10 (IL-10)), although the underlying mechanisms are not known. STAT1–STAT2 heterodimers, which are activated by type I IFNs, bind to IFN regulatory factor 9 (IRF9) in the cytosol to form the IFN-stimulated gene factor 3 (ISGF3) complex, which in turn migrates to the nucleus to bind to IFN-stimulated response elements (ISREs) and activate antiviral and antibacterial genes. In addition, type I IFNs stimulate IL-10 production either through the phosphoinositide 3-kinase (PI3K)–AKT pathway or through STAT3 homodimers. Finally, in a STAT-independent manner, type I IFNs activate both p38, which is an upstream activator of several genes regulated by ISREs and GAS elements, and mammalian target of rapamycin (mTOR), which regulates mRNA translation. CREB, cAMP-responsive-element-binding protein; IFNAR, IFNα/β receptor; IFNGR, IFNγ receptor; JAK, Janus kinase; SBE, STAT3-binding element; TBX21, T box 21; TYK2, non-receptor tyrosine kinase 2.

Figure 2. Type I IFNs regulate inflammasome activation

a | Type I interferons (IFNs) inhibit the production of IL-1β by the inflammasome through two different mechanisms. First, they activate signal transducer and activator of transcription 1 (STAT1), which directly inhibits the NOD-, LRR- and pyrin domain-containing 1 (NLRP1) and NLRP3 inflammasomes but not the absent in melanoma 2 (AIM2) or NOD-, LRR- and CARD-containing 4 (NLRC4) inflammasomes. Second, type I IFNs induce the production of interleukin-10 (IL-10), which binds to the IL-10 receptor (IL-10R) in an autocrine manner and activates STAT3, which in turn reduces the levels of the precursors pro-IL-1α and pro-IL-1β. b | Type I IFN signalling is required for efficient activation of the AIM2 inflammasome in response to Francisella tularensis. After the bacterium enters the phagosome, the phagosome is rapidly acidified. Acidification causes the release of bacterial DNA into the cytosol, and this DNA activates an unidentified DNA sensor, which in turn activates IFN regulatory factor 3 (IRF3) to initiate the production of type I IFNs. IFNβ then binds to the IFNα/β receptor (IFNAR) in an autocrine manner to enhance the activation of the AIM2 inflammasome, possibly by increasing phagosomal acidification and/or bactericidal activity, thereby favouring the release of more bacterial DNA. CREB, cAMP-responsive-element-binding protein; TLR, Toll-like receptor.

Figure 3. IL-1R1 signalling regulates type I IFN production

Interleukin-1 receptor 1 (IL-1R1) signalling positively modulates the production of type I interferons (IFNs) through the differential ubiquitylation of TNF receptor-associated factor 3 (TRAF3). Lysine 48 (K48)-linked polyubiquitylation of TRAF3 leads to its proteosomal degradation and the production of pro-inflammatory cytokines. By contrast, K63-linked polyubiquitylation of TRAF3 triggers the activation of IFN regulatory factor 3 (IRF3) and the subsequent production of type I IFNs. The absence of IL-1 signalling results in increased levels of deubiquitylating enzyme A (DUBA), which cleaves the K63-linked but not the K48-linked ubiquitin chains on TRAF3. LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; TLR, Toll-like receptor.

Figure 4. Type I IFNs in human diseases

Type I interferons (IFNs) are implicated in different human diseases, although their role in each condition varies. Type I IFNs usually have a beneficial impact in inflammatory syndromes, such as inflammatory bowel disease (IBD) and multiple sclerosis. By contrast, some autoimmune diseases, such as psoriasis and systemic lupus erythematosus (SLE), are improved by type I IFN inhibition. This figure summarizes the positive (green) and negative (red) roles of type I IFNs in different human conditions. IL-10, interleukin-10; T_H, T helper.