The Absent in Melanoma 2-Like Receptor IFN-Inducible Protein 16 as an Inflammasome Regulator in Systemic Lupus Erythematosus: The Dark Side of Sensing Microbes

Abstract

Absent in melanoma 2 (AIM2)-like receptors (ALRs) are a newly characterized class of pathogen recognition receptors (PRRs) involved in cytosolic and nuclear pathogen DNA recognition. In recent years, two ALR family members, the interferon (IFN)-inducible protein 16 (IFI16) and AIM2, have been linked to the pathogenesis of various autoimmune diseases, among which systemic lupus erythematosus (SLE) has recently gained increasing attention. SLE patients are indeed often characterized by constitutively high serum IFN levels and increased expression of IFN-stimulated genes due to an abnormal response to pathogens and/or incorrect self-DNA recognition process. Consistently, we and others have shown that IFI16 is overexpressed in a wide range of autoimmune diseases where it triggers production of specific autoantibodies. In addition, evidence from mouse models supports a model whereby ALRs are required for IFN-mediated host response to both exogenous and endogenous DNA. Following interaction with cytoplasmic or nuclear nucleic acids, ALRs can form a functional inflammasome through association with the adaptor ASC [apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)] and with procaspase-1. Importantly, inflammasome-mediated upregulation of IL-1β and IL-18 production positively correlates with SLE disease severity. Therefore, targeting ALR sensors and their downstream pathways represents a promising alternative therapeutic approach for SLE and other systemic autoimmune diseases.

Keywords: IFN-inducible protein 16; absent in melanoma 2 (AIM2)-like receptor; inflammasome; interferon; systemic lupus erythematosus.

Figure 1

Domain organization of the IFN-inducible protein 16 (IFI16). From the N- to the C-terminal (left to right), IFI16 comprises a pyrin domain (PYD) involved in protein–protein interactions, a linker region containing four nuclear localization signal motifs (NLS) and two hematopoietic interferon-inducible nuclear protein with 200-amino-acid repeats (HIN200) domains, which is an hallmark of the absent in melanoma 2-like receptors/PYHIN proteins. The HIN200 domains include two tandem b-barrels, known as oligonucleotide–oligosaccharide-binding (OB) fold, which allow DNA docking in a non-sequence-specific manner. They are separated by serine/threonine/proline-rich (S/T/P) repeats, which are regulated by alternative mRNA splicing. The numbers represent the amino acid positions based on NCBI Reference Sequence NP_005522.2.

Figure 2

An overview of the different classes of cytoplasmic and nuclear pathogen recognition receptors (PRRs) and their involvement with inflammasome activation. From left to right, a nucleotide-binding oligomerization domain-like receptor (NLR, e.g., NLRP3), an absent in melanoma 2 (AIM2)-like receptor (ALR, e.g., IFI16), and a retinoic acid inducible gene I (RIG-I)-like receptor (RLR, e.g., RIG-I), with their commonest ligands. See text for details. Abbreviations: ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD); MAVS, mitochondrial antiviral signaling protein.

Figure 3

Role of IFN-inducible protein 16 (IFI16) as inflammasome regulator in viral infections and autoimmunity. In unstimulated cells, IFI16 is mainly nuclear (upper panel). Following viral DNA recognition and binding, IFI16 can induce the activation of the canonical inflammasome through the recruitment of ASC and pro-caspase 1, and the production of type I IFN (IFN-I) through the STING–IRF axis (middle panel). In the course of autoimmune (e.g., systemic lupus erythematosus) and autoinflammatory conditions, following the recognition of self-DNA, IFI16 might be responsible for the production of pro-inflammatory cytokines and IFN-I through the same pathways. Moreover, its aberrant expression can also lead to the extracellular leakage causing amplification of the inflammatory signals and production of protective autoantibodies (lower panel). See text for details. Abbreviations: cGAS, cyclic GMP-AMP synthase; IRF3, interferon regulatory factor 3; ISG, interferon stimulated genes; STING, stimulator of interferon genes; TBK1, TANK-binding kinase.