Molecular biology of autoinflammatory diseases

The long battle between humans and various physical, chemical, and biological insults that cause cell injury (e.g., products of tissue damage, metabolites, and/or infections) have led to the evolution of various adaptive responses. These responses are triggered by recognition of damage-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns (PAMPs), usually by cells of the innate immune system. DAMPs and PAMPs are recognized by pattern recognition receptors (PRRs) expressed by innate immune cells; this recognition triggers inflammation. Autoinflammatory diseases are strongly associated with dysregulation of PRR interactomes, which include inflammasomes, NF-κB-activating signalosomes, type I interferon-inducing signalosomes, and immuno-proteasome; disruptions of regulation of these interactomes leads to inflammasomopathies, relopathies, interferonopathies, and proteasome-associated autoinflammatory syndromes, respectively. In this review, we discuss the currently accepted molecular mechanisms underlying several autoinflammatory diseases.


Background
The human body has evolved various adaptive responses that protect against cell and tissue damage caused by physical, chemical, and biological factors. Such factors include molecules released by damaged tissues, metabolites, and/or infection (e.g., by bacteria, viruses, and parasites) [1][2][3][4]. Inflammation, an adaptive response to cell injury, generates damage-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns (PAMPs), which are then recognized by pattern recognition receptors (PRRs) expressed mainly by innate immune cells [5]. PRRs include Toll-like receptors (TLRs), Nod-like receptors (NLRs), C-type lectin receptors (CLRs), and RIG-I-like receptors (RLRs) that recognize DAMPs and PAMPs to initiate immune responses. These receptors are also called innate immune receptors [6] (Fig. 1).
Corresponding common diseases caused by the similar signaling are shown in Table 1.

NLRP12 autoinflammatory syndrome
NLRP12 inhibits the activation of NF-κB. Mutations in NLRP12 are found in patients with hereditary periodic fever syndrome, the clinical signs of which are consistent with a diagnosis of CAPS [101]. Currently, 79 variants of the gene encoding NLRP12 have been reported (https:// infevers.umai-montpellier.fr/web/search.php?n=9). Since some patients with gain-of-function mutations in NLRP12 exhibit symptoms similar to those of CAPS, the Cryopyrin-associated periodic fever syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), and autoinflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) are related to NLRP3 inflammasome. Gain-of-function mutations of NLRP3 (e.g., R260W) leads to prolonged activation of NLRP3 inflammasome. Autoinflammatory syndrome caused by the gain of function of NLRP1, NLRP12, or other NLRP mutations is thought to be basically caused by the same mechanisms. Mutated TNFRSF1A (TNFR) in patients with TRAPS is misfolded and accumulated in the endoplasmic reticulum (ER), causing ER stress and increased generation of mitochondrial reactive oxygen species (ROS) that activates the NLRP3 inflammasome. PLCγ2 mutation in patients with APLAID (e.g., S707Y) leads to calcium influx from the ER and increased cytoplasmic Ca2+ levels promote activation of NLRP3 inflammasome Gout [42] Atherosclerosis [43] Type 2 diabetes [44] Neurodegenerative disease: Alzheimer's disease [45,46] Parkinson's disease [47] Amyotrophic lateral sclerosis [48] Multiple sclerosis [49] Infections and aberrant inflammatory responses: Septic shock syndrome [50,51] Ischemic diseases: Myocardial infarction [52] Stroke [53] NAIAD NLRP1 PRR against Anthrax toxin detection

Infections and aberrant inflammatory responses:
Interstitial lung disease [86] Capillaritis [87] PRAAS/NNS/CANDLE PSMB3,4,8,9 Proteasome for antigen processing Infections and aberrant inflammatory responses: SLE and other autoimmune disease [87,88] Cytomegalovirus infection [89] Hepatitis B virus infection [90] Influenza virus infection [91] disease was named FCAS2 [102] and patients with NALP12 periodic fever syndrome respond to canakinumab (an anti-human IL-1β monoclonal antibody) and/or etanercept (a tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein that acts as a bivalent antagonist of TNF activity) [102], the pathogenesis of NLRP12 autoinflammatory syndrome (NLRP12-AD) may explain the gain of function of the NLRP12 inflammasome by a similar mechanism of the NLRP3 inflammasome ( Fig. 2). Corresponding common diseases caused by the similar signaling are shown in Table 1.

TNF receptor-associated periodic fever syndrome
The causative gene product of TNF receptor-associated periodic fever syndrome (TRAPS) is TNF receptor superfamily member 1A (TNFRSF1A) [12]. So far, 180 variations of the TNFRSF1A gene have been reported (https://infevers.umai-montpellier.fr/web/search.php?n= 2). The cysteine-to-cysteine disulfide bonds in the extracellular domain of TNFRSF1A for ER stress are thought to be important for disease pathogenesis. More than one-third of patients with TRAPS harbor the R92Q and P46L mutations [103]. In TRAPS, misfolding of mutated TNFRSF1A leads to accumulation of the protein in the endoplasmic reticulum (ER), which causes ER stress and increased generation of mitochondrial reactive oxygen species; this in turn activates inflammasomes [104,105] ( Fig. 2). Corresponding common diseases caused by the similar signaling are shown in Table 1.
Autoinflammation and phospholipase Cγ2-associated antibody deficiency and immune dysregulation Autoinflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) responds to PLCγ2 which encodes for a constitutively repressed phospholipase. The S707Y PLCγ2 mutation disrupts the autoinhibition of PLCγ2, thereby increasing PLCγ2 activity and calcium influx from the ER in the leukocytes of patients with APLAID [106,107]. Increased cytoplasmic Ca2+ levels promote the assembly of the NLRP3 inflammasome [108] (Fig. 2). Corresponding common diseases caused by the similar signaling are shown in Table 1.

Familial Mediterranean fever
The causative gene of familial Mediterranean fever (FMF), MEFV, encodes pyrin (also named marenostrin) [109,110]. Currently, 389 variants of MEFV have been reported (https://infevers.umai-montpellier.fr/web/ search.php?n=1). FMF was reported to be autosomal recessive; mutations in pyrin are thought to result in loss of its ability to inhibit inflammasomes. Nowadays, pyrin assembles with ASC and pro-caspase-1 to form the pyrin inflammasome, as well as the NLRP3 inflammasome [111]. Usually, pyrin is phosphorylated by serine/ threonine-protein kinases PKN1 and PKN2, and inhibited by 14-3-3 proteins. When virulence factors expressed or secreted by bacteria and/or viruses inhibit RhoA GTPase, the pyrin inflammasome triggers activation and secretion of IL-1β [112] (Fig. 3). Yersinia pestislike bacteria have a YopM protein which interacts with pyrin to inhibit inflammatory responses for avoiding further anti-bacterial responses [113]. In patients with FMF, pyrin harboring mutant human B30.2 domains defect such kind of ability, thereby preventing binding to ASC; this makes prolonged inflammasome activation and IL-1β secretion [114] (Fig. 3). Corresponding common diseases caused by the similar signaling are shown in Table 1.

Periodic fever immunodeficiency and thrombocytopenia
The causative gene product of periodic fever immunodeficiency and thrombocytopenia (PFIT) is WDR1 [115,116], which interacts with cofilin to promote cleavage and depolymerization of F-actin [117,118]. The L293F mutation in WDR1 disrupts intramolecular hydrophobic SLE and other autoimmune diseases [75,76,94] Paramyxovirus infection [82] Picornavirus infection [83] RIG-I PRR for viral RNA detection Infections and aberrant inflammatory responses: SLE and other autoimmune diseases [95] Paramyxovirus infection [83] interactions, which are important for maintaining actin protein structure. This disruption leads to actin accumulation and aggregates with pyrin resulting in pyrin activation and release of IL-18 [119] (Fig. 4). Corresponding common diseases caused by the similar signaling are shown in Table 1.

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome
The causative gene product of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is proline-serinethreonine phosphatase-interacting protein 1 (PSTPIP1) (also called CD2-binding protein 1 (CD2BP1)) [124,125]. Currently, 66 variants of the PSTPIP1 gene have been reported (https://infevers.umai-montpellier.fr/web/search.php?n=5). In patients with PAPA syndrome, mutations in PSTPIP1 result in hyperphosphorylation of PSTPIP1, which strengthens its interaction with pyrin via the B-box domain to activate the pyrin inflammasome. This leads to increased secretion of IL-  (Fig. 6). Corresponding common diseases caused by the similar signaling are shown in Table 1.

Mevalonate kinase deficiency/hyper-IgD syndrome
The causative gene product of mevalonate kinase deficiency/hyper-IgD syndrome (MKD) (also known as hyper-IgD syndrome (HIDS)) is mevalonate kinase (MVK) [126]. Currently, 264 variants of this gene have been reported (https://infevers.umai-montpellier.fr/web/ search.php?n=3). Geranylgeranyl pyrophosphate, the substrate of geranylgeranylation, is a product of the mevalonate pathway. Deficiency of MVK leads to depletion of geranylgeranyl pyrophosphate, resulting in the inactivation of RhoA [127,128]. Since the inactivation of RhoA activates the pyrin inflammasome, MKD leads to an inflammasomopathy. Indeed, canakinumab, an anti-IL-1β monoclonal antibody, is an effective treatment for MKD, suggesting that IL-1β is a common mediator of these diseases [129] (Fig. 7). Corresponding common diseases caused by the similar signaling are shown in Table 1.

NLRC4 inflammasomopathies
Gain-of-function mutations in NLRC4 result in earlyonset recurrent fever and macrophage activation syndrome (MAS), neonatal-onset enterocolitis with periodic fever, fatal or near-fatal episodes of autoinflammation, or symptoms resembling those of FCAS [68,130,131]. So far, more than 31 genetic variants of NLRC4 have been reported (https://infevers.umai-montpellier.fr/web/ search.php?n=25). The NLRC4 inflammasome activates caspase-1 either with or without an adaptor ASC, which in turn activates IL-1β and IL-18. NLRC4 inflammasomopathies are linked more closely with hypersecretion of IL-18 rather than of IL-1β; however, the precise mechanism remains to be elucidated [132] (Fig. 8). Corresponding common diseases caused by the similar signaling are shown in Table 1.

OTULIN-related autoinflammatory syndrome
OTULIN is a deubiquitination enzyme that hydrolyzes methionine-1 (M1), which links to liner ubiquitin chains to regulate the activity of NF-κB [149]. Homozygous loss-of-function mutations in OTULIN cause OTULINrelated autoinflammatory syndrome (ORAS) [150]. The L272P mutation is located in a helix of the catalytic OTU domain, which forms part of the binding pocket for M1-linked distal ubiquitin; this mutation disrupts the binding of OTULIN and ubiquitin to its substrate [151,152] (Fig. 13). Corresponding common diseases caused by the similar signaling are shown in Table 1.

Interferonopathies
Anti-viral first-line defense is dependent on innate immune receptors (e.g., cGAS, MDA5, and RIG-I) that are detecting intracellular viral, bacterial, or own nucleic acid, linking to type I interferon signaling. Interferonopathies are closely linked to dysfunction of these innate immune receptors and type I interferon signaling, Immunoproteasome dysfunction is also linked to the interferonopathies [157] (Fig. 14).

Aicardi-Goutières syndrome
Aicardi-Goutières syndrome (AGS) is an inherited encephalopathy that affects newborn infants and usually results in severe neuro-physical disability. AGS is caused by loss-of-function mutations in the genes encoding the three prime repair exonuclease 1 (TREX1), the ribonuclease H2 subunit (RNASEH2)A, RNASEH2B, RNA-SEH2C, the phosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1), or the dsRNAspecific adenosine deaminases acting on RNA1 (ADAR1) [158,159]. In addition, gain-of-function mutations in the dsRNA sensor MDA5 (also called IFIH1) have been identified in AGS patients [157]. AGS pathology seems to be caused by the accumulation of nucleic acids, which can cause neurological and liver abnormalities that resemble congenital viral infection (Fig. 15). Corresponding common diseases caused by the similar signaling are shown in Table 1.

Stimulator of interferon gene-associated vasculopathy with onset in infancy
Stimulator of interferon gene (STING)-associated vasculopathy with onset in infancy (SAVI) is caused by gain-offunction mutations in STING (also called TMEM173). Mutation of the STING amplifies the function of STING, which is an adaptor molecule involved in signal transduction through cGAS, leading to hyperactivation of type I IFN pathways [160]. Corresponding common diseases caused by the similar signaling are shown in Table 1.

Coatomer protein alpha syndromes
Coatomer protein alpha (COPA) syndrome, characterized by high-titer autoantibodies, interstitial lung disease, and inflammatory arthritis, was found to be deleterious mutations in the COPA gene (encoding coatomer subunit α). Mutant COPA causes defective intracellular transport via coat protein complex I which leads to ER stress and the upregulation of the levels of transcripts encoding IL-1β, IL-6, and IL-23 [161]. COPA is a critical regulator of STING transport ER and retrieval of STING from the Golgi. Mutant COPA retention of STING on the Golgi resulting in STING activation leads to prolonged type I interferon signaling [86] (Fig. 16). Corresponding common diseases caused by the similar signaling are shown in Table 1.

Proteasome-associated autoinflammatory syndromes
Nakajo-Nishimura syndrome (NNS) and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE) were the first PRAAS to be described. Loss-of-function mutation in immunoproteasome components such as proteasome subunit beta type (PSMB)8, PSMB4, PSMA3, PSMB9, or proteasome maturation protein (POMP) leads to increased secretion of type I IFN by immune cells [162,163] (Fig. 17). Corresponding common diseases caused by the similar signaling are shown in Table 1.

Singleton-Merten syndrome
Singleton-Merten syndrome (SMS) is caused by gain-offunction mutations in the RNA sensor MDA5 or RIG-I. Typical SMS is caused by a mutation in MDA5, whereas atypical SMS is caused by a mutation in RIG-I; both mutations cause constitutive activation of IFN signaling pathways [164,165]. Notably, mutations in the MDA5 are also associated with AGS, so that both SMS and AGS share a common molecular mechanism [164] ( Fig. 18). Corresponding common diseases caused by the similar signaling are shown in Table 1.

Conclusions
Here, we describe briefly the molecular mechanisms underlying autoinflammatory diseases caused by dysregulation of IL-1β or IL-18 processing, NF-κB activation, Fig. 11 NF-κB activation pathway in patients with A20 protein haploinsufficiency (HA20). Loss-of-function mutations of A20 (e.g., L227X) reduce the deubiquitination activity of A20 leading to prolonged activation of NF-κB