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.

Valeria Caneparo,Marco De Andrea,Santo Landolfo,Marisa Gariglio

doi:10.3389/fimmu.2018.01180

Valeria Caneparo, Marco De Andrea + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2018.01180

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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.

Highlights

Inflammation is an innate immune response largely mediated by phagocytic cells whose goal is to protect the body from invading bacteria and viruses [1, 2]
Pattern recognition receptors (PRRs) constitute a large family of molecules expressed on the cell surface and in the cytoplasm of various cell types, such as macrophages and antigen presenting cells (APC), able to interact with evolutionarily conserved pathogenic structures [i.e., pathogen-associated molecular patterns (PAMPs)], IFI16 and Inflammasome in systemic lupus erythematosus (SLE)
Chronic inflammatory responses, which could last for weeks or even years, are characterized by episodes of tissue injury and healing resulting in severe tissue damage, which can eventually lead to the development of autoinflammatory/autoimmune diseases such as systemic lupus erythematosus (SLE) [13,14,15]

Summary

Introduction

Inflammation is an innate immune response largely mediated by phagocytic cells whose goal is to protect the body from invading bacteria and viruses [1, 2]. SLE is characterized by AIM2 inflammasome-mediated production of IL-1β, triggered by accumulation of cytosolic self-DNA and IFI16-induced IFN-I release [40].

Results

Conclusion