Interferon lambda in inflammation and autoimmune rheumatic diseases

Abstract

Interferons are potent antiviral cytokines that modulate immunity in response to infection or other danger signals. In addition to their antiviral functions, type I interferons (IFNα and IFNβ) are important in the pathogenesis of autoimmune diseases. Type III interferons (IFNλs) were initially described as a specialized system that inhibits viral replication at epithelial barrier surfaces while limiting inflammatory damage. However, evidence now suggests that type III interferons have complex effects on both innate and adaptive immune responses and might also be pathogenic in systemic autoimmune diseases. Concentrations of IFNλs are increased in blood and tissues in a number of autoimmune rheumatic diseases, including systemic lupus erythematosus, and are further associated with specific clinical and laboratory parameters. This Review is aimed at providing a critical evaluation of the current literature on IFNλ biology and how type III interferons might contribute to immune dysregulation and tissue damage in autoimmunity. The potential effects of type III interferons on treatment strategies for autoimmune rheumatic diseases, such as interferon blockade, are also considered.

Fig. 1. Type I and type III interferon signalling pathways.

Type I and type III interferons can activate both Janus kinase 1 (JAK1) and non-receptor tyrosine-protein kinase TYK2 (TYK2), leading to signal transducer and activator of transcription (STAT) phosphorylation and the formation of STAT1–STAT2 heterodimers. These heterodimers can interact with interferon regulatory factor 9 (IRF9) to form the interferon stimulated gene factor 3 (ISGF3) transcription factor complex. ISGF3 translocates to the nucleus, where it can bind to interferon-stimulated regulatory element (ISRE) sequences and promote the expression of interferon-stimulated genes (ISGs). Type III interferons comparatively induce lower amplitude expression of ISGs over a longer period of time than type I interferons, possibly owing to differential negative regulation by Ubl carboxyl-terminal hydrolase 18 (USP18). Type I and type III interferons can also promote the formation of STAT1 homodimers, which upregulate IRF1 expression and lead to pro-inflammatory chemokine production. IFNλ can also signal through a variety of non-canonical mechanisms. GAS, IFNγ-activated sequence; IFN, interferon; IFNAR, IFNα receptor; IFNLR1, IFNλ receptor 1; IL-10RB, IL-10 receptor subunit-β.

Fig. 2. IFNλs in skin disease in systemic lupus erythematosus.

Danger signals, including Toll-like receptor 7 (TLR7) agonists and RNA-containing immune complexes (RNA-IC), can induce the production of IFNλs by plasmacytoid dendritic cells. TLR3 agonists can also induce the production of IFNλs by keratinocytes. IFNλs can subsequently activate keratinocytes to upregulate the expression of the chemokines CXCL9, CXCL10 and CXCL11, as well as surface MHC class I molecules. These chemokines recruit CXCR3⁺ leukocytes to the skin, where they promote tissue damage; in particular, cytotoxic CD8⁺ T cells can cause keratinocyte cell death. The release of endogenous nucleic acids (in combination with the cathelicidin LL-37 in experimental models) can induce further production of IFNλs, resulting in a feed-forward loop that perpetuates inflammation in the skin. Whether inflammatory stimuli can also upregulate IFNλ receptor (IFNLR) expression on keratinocytes is unclear. NET, neutrophil extracellular trap.

Fig. 3. Interferon blockade for autoimmune rheumatic diseases.

Biologic agents that target IFNα or IFNα receptor (IFNAR) can block the effects of type I interferons but have no effect on type III interferons. Drugs targeting interferon production by plasmacytoid dendritic cells (such as anti-BDCA2 or anti-LILR4A antibodies), or downstream Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling in target cells (such as JAK inhibitors), can block both type I and type III interferons. BDCA2, blood dendritic cell antigen 2; IFN, interferon; IFNGR1, IFNγ receptor 1; IFNGR2, IFNγ receptor 2; IFNLR1, IFNλ receptor 1; IL-10RB, IL-10 receptor subunit-β; LILR4A, leukocyte immunoglobulin-like receptor subfamily A member 4; TYK2, non-receptor tyrosine-protein kinase TYK2.