Molecular biology of autoinflammatory diseases
Inflammation and Regeneration volume 41, Article number: 33 (2021)
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.
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 . 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  (Fig. 1).
Autoinflammatory diseases are strongly associated with dysregulation of these PRR-containing interactomes, which include inflammasomes, nuclear factor (NF)-κB-activating signalosomes, type I interferon-inducing signalosomes, and immuno-proteasomes; dysfunction of these interactomes results in inflammasomopathies, relopathies, interferonopathies, and proteasome-associated autoinflammatory syndromes (PRAAS), respectively [7,8,9,10,11]. This explains the pathogenesis of autoinflammatory diseases involving recurrent inflammatory flare-ups in the absence of autoantibodies or antigen-specific T lymphocytes . Knowledge of the molecular mechanism(s) underlying the functions of these innate immune receptors is useful for the treatment and management of individuals with autoinflammatory diseases (Fig. 1).
Interleukin-1β-mediated autoinflammatory diseases (inflammasomopathies)
When NOD-like receptors harboring a PYRIN domain (PYD) (e.g., NLRP1, NLRP2, NLRP3, NLRP6, NLRP9, and NLRP12) and other pyrin domain-containing PRRs (e.g., pyrin, AIM2, and IFI-16) sense DAMPs, PAMPs, or intracellular microenvironmental changes (e.g., potassium efflux), they interact with an adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) via PYD, and pro-caspase-1 via a caspase-recruitment domain (CARD). This interaction activates caspase-1, a process accompanied by pyroptotic cell death [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]. NOD-like receptors carrying a CARD domain or CARD including proteins alternatively interact with caspase-1 via CARD with ASC and pro-caspase-1 such as NLRP1, NLRC4, CARD8, and caspase-11 [30,31,32]. The resulting complexes act as a sensor of cell injury; this sensor is referred to as the inflammasome, an interleukin (IL)-1β- and IL-18-processing platform that plays a crucial role in the maturation and secretion of these cytokines from cells. The process is accompanied by a type of cell death, named pyroptosis, which is triggered by cleavage of gasdermin D (GSDMD) [33, 34] (Fig. 2). Below, we discuss specific inflammasomopathies.
Cryopyrin-associated periodic syndrome
Cryopyrin is the same protein as NLRP3 which was named by the nomenclature committee. Gain-of-function mutations in NLRP3 lead to cryopyrin-associated periodic syndrome (CAPS), a spectrum of diseases that includes familial cold autoinflammatory syndrome (FCAS, formerly termed familial cold urticaria (FCU)), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID; also called chronic infantile neurologic cutaneous and articular syndrome (CINCA)). Currently, 248 variants of the CIAS1 gene have been reported by “INFEVERS” (https://infevers.umai-montpellier.fr/web/search.php?n=4) . The NLRP3 mutations in CAPS result in constitutive activation of the NLRP3 inflammasome (i.e., the threshold for stimulation is extremely low). Activation of the inflammasome leads to excess pyroptosis of cells expressing components of the NLRP3 inflammasome; these cells secrete excessive amounts of activated IL-1β upon autoinflammatory attack [36,37,38,39,40,41] (Fig. 2). Corresponding common diseases caused by the similar signaling are shown in Table 1.
NLRP1-associated autoinflammation with arthritis and dyskeratosis
The NLRP1 inflammasome was the first “inflammasome” to be identified . NLRP1 interacts with ASC through its PYD domain. ASC then interacts with pro-caspase-1 via its CARD domain, resulting in activation of IL-1β secretion; also, NLRP1 interacts with caspase-1 through its CARD domain to activate IL-1β secretion . Currently, several mutations (A54T, A59P, A66V, M77T, R726W, T755N, F787_R843del, and P1214R) in the gene encoding NLRP1 have been identified (https://infevers.umai-montpellier.fr/web/search.php?n=31). Patients harboring these mutations exhibit dyskeratosis, oligo/polyarthritis, and recurrent fever, along with immunological dysfunction and vitamin A deficiency [97,98,99]. The mutations may trigger proteasome-dependent functional degradation of NLRP1, and degraded CARD-FIIND-containing-NLRP1 fragments act as a scaffold like ASC for inflammasome activation  (Fig. 2). 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 . 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 disease was named FCAS2  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) , 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) . 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 . 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  (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 . 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  (Fig. 3). Yersinia pestis-like bacteria have a YopM protein which interacts with pyrin to inhibit inflammatory responses for avoiding further anti-bacterial responses . 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  (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 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  (Fig. 4). Corresponding common diseases caused by the similar signaling are shown in Table 1.
Pyrin-associated autoinflammation with neutrophilic dermatosis
The MEFV mutations in patients with pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) harbor S242R and E244K mutations in pyrin; these mutations are located in the 14-3-3 binding motif, which interferes with binding of pyrin to 14-3-3, thereby allowing assembly of the pyrin inflammasome and excessive release of IL-1β [120,121,122,123] (Fig. 5). 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-serine-threonine 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-1β  (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) . 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  (Fig. 7). Corresponding common diseases caused by the similar signaling are shown in Table 1.
Gain-of-function mutations in NLRC4 result in early-onset 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  (Fig. 8). Corresponding common diseases caused by the similar signaling are shown in Table 1.
NF-κB-related autoinflammatory diseases (relopathies)
Dysregulations of NF-κB signaling are closely linking to the ubiquitination system. In addition to constitutive activation of NF-κB, loss-of-function mutations in the ubiquitin-mediated NF-κB regulatory system cause autoinflammatory diseases  (Fig. 9).
Blau syndrome/early-onset sarcoidosis
The gene responsible for Blau syndrome (BS)/early-onset sarcoidosis (EOS) is IBD1, and its causative gene product is NOD2 . Usually, NOD2 recognizes muramyl dipeptide (MDP), leading to activation of NF-κB. Currently, 185 variants of NOD2 have been reported (https://infevers.umai-montpellier.fr/web/search.php?n=6). Gain-of-function mutations in NOD2 increase signaling via NOD2-RIPK2-associated activation of NF-κB [134, 135] (Fig. 10). Corresponding common diseases caused by the similar signaling are shown in Table 1.
A20 protein haploinsufficiency
A20 (also called TNF-α-induced protein (TNFAIP) 3, is an intracellular deubiquitinase. A20 plays a role in deubiquitination of several proteins, including NF-κB. A20 protein haploinsufficiency (HA20) is caused by heterozygous mutation or deletion of A20, resulting in insufficient deubiquitination of TRAF6 downstream of the TNF-α pathway, RIPK1 downstream of the TLR pathway, and RIPK2 downstream of the NOD1 or NOD2 pathways. Loss of A20 function leads to constitutive activation of NF-κB signaling [136, 137]. A20 also regulates the activity of the NLRP3 inflammasome in macrophages . So far, 55 variants of A20 have been reported (https://infevers.umai-montpellier.fr/web/search.php?n=26). Haplodeficient mutations severely reduce A20 function, leading to prolonged activation of NF-κB  (Fig. 11). Corresponding common diseases caused by the similar signaling are shown in Table 1.
Immunodeficiency, autoinflammation, and amylopectinosis with inherited linear ubiquitin chain assembly complex deficiency
Loss-of-function mutation in linear ubiquitin chain assembly complex (LUBAC), a protein complex comprising heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1) (also called RBCK1), HOIL-1 interaction protein (HOIP, also called RNF31), and SHANK-associated RH domain-interacting protein (SHARPIN) is associated with autoinflammation [140,141,142,143,144,145]. The L72P mutation in the HOIP protein affects its interaction with OTU deubiquitinase with linear linkage specificity (OTULIN) and lysine 63 deubiquitinase (CYLD); however, the most common disease-causing phenomenon is loss of expression of the L72P allele of HOIP. Combined heteromutations comprise L41fsX7 and Q185X, which result in deficient HOIL-1 expression. Lack of HOIL-1 expression by fibroblasts impairs phosphorylation of IKK kinase, slower degradation of IκBα, and decreased ubiquitination of NEMO in response to stimulation with either TNF-α or IL-1β. LUBAC deficiency in fibroblasts downregulates NF-κB activation in response to IL-1β or TNF-α, whereas deficient monocytes release more IL-6 but less IL-10 in response to IL-1β [146,147,148] (Fig. 12). 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 . Homozygous loss-of-function mutations in OTULIN cause OTULIN-related autoinflammatory syndrome (ORAS) . 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.
IL-1 receptor-related autoinflammatory diseases
IL-1 receptor-related autosomal recessive autoinflammatory diseases are caused by mutations in IL1RN (interleukin-1 receptor antagonist), resulting in a condition called deficiency of interleukin-1 receptor antagonist (DIRA) [153,154,155]. So far, 22 variants of this gene have been reported (https://infevers.umai-montpellier.fr/web/search.php?n=10). IL-1RA deficiency results in uncontrolled IL-1α, IL-1β and NF-κB signaling  (Fig. 9). Corresponding common diseases caused by the similar signaling are shown in Table 1.
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  (Fig. 14).
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, RNASEH2C, the phosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1), or the dsRNA-specific 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 . 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-of-function 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 . 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 . 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  (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 (SMS) is caused by gain-of-function 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  (Fig. 18). Corresponding common diseases caused by the similar signaling are shown in Table 1.
Here, we describe briefly the molecular mechanisms underlying autoinflammatory diseases caused by dysregulation of IL-1β or IL-18 processing, NF-κB activation, and IFN secretion. Disruption of the fine balance within these signaling pathways contributes to the pathogenesis of autoinflammatory diseases. Increasing our knowledge of the molecular biology underlying autoinflammatory diseases will facilitate the development of disease-targeting biologics. Therefore, future studies should elucidate the autoinflammatory disease-specific signalosome in detail.
Availability of data and materials
Damage-associated molecular pattern
Pathogen-associated molecular pattern
Pattern recognition receptor
C-type lectin receptor
Proteasome-associated autoinflammatory syndromes
Absent in melanoma 2
Apoptosis-associated speck-like protein containing a caspase-recruitment domain
Cryopyrin-associated periodic syndrome
Familial cold autoinflammatory syndrome
Familial cold urticaria
Neonatal-onset multisystem inflammatory disease
Chronic infantile neurologic, cutaneous, and arthritis
NLRP1-associated autoinflammation with arthritis and dyskeratosis
NLRP12 autoinflammatory syndrome
Tumor necrosis factor
TNF receptor-associated periodic fever syndrome
TNF receptor superfamily member
Autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation
Familial Mediterranean fever
Periodic fever immunodeficiency and thrombocytopenia
Pyrin-associated autoinflammation with neutrophilic dermatosis
Pyogenic arthritis, pyoderma gangrenosum, and acne
Proline-serine-threonine phosphatase-interacting protein 1
CD2-binding protein 1
Mevalonate kinase deficiency
Hyperimmunoglobulinemia D and periodic fever syndrome
Macrophage activation syndrome
A20 protein haploinsufficiency
Tumor necrosis factor alpha-induced protein
Immunodeficiency, autoinflammation, and amylopectinosis with inherited linear ubiquitin chain assembly complex deficiency
Linear ubiquitin chain assembly complex
Heme-oxidized IRP2 ubiquitin ligase 1
HOIL-1 interaction protein
SHANK-associated RH domain-interacting protein
OTU deubiquitinase with linear linkage specificity
CYLD lysine 63 deubiquitinase
OTULIN-related autoinflammatory syndrome
Deficiency of the IL-1-receptor antagonist
Three prime repair exonuclease
Ribonuclease H2 subunit
SAM domain and HD domain-containing protein
dsRNA-specific adenosine deaminases acting on RNA 1
Stimulator of interferon genes
STING-associated vasculopathy with onset in infancy
Coatomer protein alpha
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome
Proteasome subunit beta type
Proteasome maturation protein
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We greatly appreciate Dr. Isabelle Touitou, chief editor of “INFEVERS” database, and its contributors.
This work was supported by Grants-in-Aid for Scientific Research (B) (JSPS KAKENHI Grant Number: 20H03719 to JM) and Grant-in-Aid for Encouragement of Scientists (JSPS KAKENHI Grant Number: 20H01085 to NK).
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Masumoto, J., Zhou, W., Morikawa, S. et al. Molecular biology of autoinflammatory diseases. Inflamm Regener 41, 33 (2021). https://doi.org/10.1186/s41232-021-00181-8