Pathogenic insights from genetic causes of autoinflammatory inflammasomopathies and interferonopathies

Abstract

A number of systemic autoinflammatory diseases arise from gain-of-function mutations in genes encoding IL-1-activating inflammasomes or cytoplasmic nucleic acid sensors including the receptor and sensor STING and result in increased IL-1 and type I interferon production, respectively. Blocking these pathways in human diseases has provided proof-of-concept, confirming the prominent roles of these cytokines in disease pathogenesis. Recent insights into the multilayered regulation of these sensor pathways and insights into their role in amplifying the disease pathogenesis of monogenic and complex genetic diseases spurred new drug development targeting the sensors. This review provides insights into the pathogenesis and genetic causes of these "prototypic" diseases caused by gain-of function mutations in IL-1-activating inflammasomes (inflammasomopathies) and in interferon-activating pathways (interferonopathies) including STING-associated vasculopathy with onset in infancy, Aicardi-Goutieres syndrome, and proteasome-associated autoinflammatory syndromes that link activation of the viral sensors STING, "self" nucleic acid metabolism, and the ubiquitin-proteasome system to "type I interferon production" and human diseases. Clinical responses and biomarker changes to Janus kinase inhibitors confirm a role of interferons, and a growing number of diseases with "interferon signatures" unveil extensive cross-talk between major inflammatory pathways. Understanding these interactions promises new tools in tackling the significant clinical challenges in treating patients with these conditions.

Keywords: Aicardi-Goutieres syndrome; Interferonopathies; JAK inhibitor; STING; inflammasome; inflammasomopathies; interferon; proteasome-associated autoinflammatory syndrome.

FIG 1.. Characteristics of various inflammasomes.

CARD domain or PYD domain is responsible for recruiting ASC and for forming ASC specks. Other domains function as regulatory domains to prevent inflammasome autoactivation (detailed in Fig 2). Diseases related to the inflammasomes are shown in the last column with the MIM numbers (www.oimm.org). Diseases in bracket typically do not present with systemic inflammation. See text for full name of the diseases. NLRP1-associated: NAIAD or AIADK; JRRP. *MSPC is caused by mutations in the pyrin domain of NLRP1 and leads to a precancerous skin condition without systemic inflammation. NLRP3-associated: The disease spectrum of CAPS includes the 3 severity phenotypes: NOMID, MWS, and FCAS. ** DFNA34, (Deafness, autosomal dominant 34) and **KEFH, (Keratoendothelitis fugax hereditaria) present with inflammation restricted to the inner ear and the cornea respectively with absent or minimal systemic inflammation. NLRC4-associated AIDs include NLRC4-MAS/AIFEC presenting with recurrent MAS and FCAS4 presenting with more systemic inflammation and rash. MEFV/pyrin-associated AIDs include additive gain-of function, AR (autosomal recessive) and AD (autosomal dominant) FMF, and PAAND/AFND caused by mutations in two 14–3-3-binding serine residues. Mutations in AIM2 and CASP4 have so far not been associated with human monogenic diseases.

FIG 2.. Mechanism of NLRP3 (A), NLRC4 (B), and NLRP1 (C) inflammasome activation.

(A) NEK7 binding and ATP exchange in NLRP3 cause a confirmation change of the NACHT domain, which allows NLRP3 oligomerization and formation of an NLRP3 disc. The PYD domains in the “disc” then recruit ASC via PYD-PYD interaction, which triggers polymer assembly of ASC. The ASC polymers can further form specks via CARD-CARD interaction between the ASC polymers. This creates a platform to recruit CASPASE1 via CARD-CARD interaction between ASC and CASPASE1. CASPASE1 is then activated by autocleavage between p20 and p10 domain, which leads to NLRP3 inflammasome activation. NLRC4 is activated in a similar way (B), except initiated by ligand binding to NAIP and the ligand/NAIP/NLRC4 disc recruits ASC via CARD-CARD interaction. (C) NLRP1 is a “booby trap” for pathogens. In an attempt to deactivate the host immune system, some pathogen lethal factors try to degrade NLRP1. However, degradation of the NLRP1 N-terminal fragment leads to release of the CARD domain which triggers NLRP1 activation. CARD domain in NLRC4 or NLRP1 can recruit ASC to form ASC specks; they can also directly recruit CASPASE1 as shown in (C), right panel, direct CASPASE1 recruitment.

FIG 3.. Interferon mediated/amplified diseases are caused by dysregulation of interferon production and signaling.

Viral replication in the cell leads to aberrant accumulation of cytosolic nucleic acids, which are sensed by the host and trigger type I/III interferon production. Cytosolic DNAs are sensed by cGAS, which produces 2’3’cGAMP, a ligand for the adaptor STING. Cytosolic RNAs are sensed by RIG-I or MDA5, which activates the adaptor MAVS. Adaptor activation leads to TBK1 phosphorylation, which phosphorylates the transcription factor IRF3 and triggers the Type I/III interferon production. Cytosolic nucleic acids are also generated in cell homeostatic processes such as DNA replication, and are degraded/reduced by various enzymes including nucleases. Mitochondrial RNAs are degraded by RNases including PNPT1. Type I and II interferons bind to their respective receptors and mediate the transcription of interferon response genes. Interferon signaling is tightly controlled by signaling suppressors including USP18, ISG15, SOCS family proteins, and STAT2, which bind to the signaling complexes for proteasome degradation. Mutations in proteasome components also lead to IFN production by yet unknown mechanisms. Disease-causing mutations in ACP5 are associated with enhanced interferon signaling, possibly via Osteopontin and IRF7. Due to space limitations, two AGS associated genes, LSM11, RNU7–1, are not shown in the figure.