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Autoinflammatory diseases are caused by defects in genes that regulate the innate immunity. Recently, the scope of autoinflammation has been broadened to include diseases that result from dysregulations in protein modifications by the highly conserved ubiquitin (Ub) peptides. Thus far these diseases consist of linear ubiquitin chain assembly complex (LUBAC) and OTULIN deficiencies, and haploinsufficiency of A20. The LUBAC is critical for linear ubiquitination of key signaling molecules in immune response pathways, while deubiquitinase enzymes, OTULIN and TNFAIP3/A20, reverse the effects of ubiquitination by hydrolyzing linear (Met1) and Lys63 (K63) Ub moieties, respectively, from conjugated proteins. Consequently, OTULIN or A20-deficient cells have an excess of Met1 or K63 Ub chains on NEMO, RIPK1, and other target substrates, which lead to constitutive activation of the NF-kB pathway. Mutant cells produce elevated levels of many proinflammatory cytokines and respond to therapy with cytokine inhibitors. Patients with an impairment in LUBAC stability have compromised NF-kB responses in non-immune cells such as fibroblasts, while their monocytes are hyperresponsive to IL-1β. Discoveries of germline mutations in enzymes that regulate protein modifications by Ub define a new category of autoinflammatory diseases caused by upregulations in the NF-kB signaling. The primary aim of this review is to summarize the latest developments in our understanding of the etiology of autoinflammation.

Immune cell activation is a stringently regulated process, as exaggerated innate and adaptive immune responses can lead to autoinflammatory and autoimmune diseases. Perhaps the best-characterized molecular pathway promoting cell activation is the nuclear factor-κB (NF-κB) signaling pathway. Stimulation of this pathway leads to transcription of numerous pro-inflammatory and cell-survival genes. Several mechanisms tightly control NF-κB activity, including the key regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor α-induced protein 3 (TNFAIP3). Single nucleotide polymorphisms (SNPs) in the vicinity of the gene are associated with a spectrum of chronic systemic inflammatory diseases, indicative of its clinical relevance. Mice harboring targeted cell-specific deletions of the gene in innate immune cells such as macrophages spontaneously develop autoinflammatory disease. When immune cells involved in the adaptive immune response, such as dendritic cells or B-cells, are targeted for A20/TNFAIP3 deletion, mice develop spontaneous inflammation that resembles human autoimmune disease. Therefore, more knowledge on A20/TNFAIP3 function in cells of the immune system is beneficial in our understanding of autoinflammation and autoimmunity. Using the aforementioned mouse models, novel A20/TNFAIP3 functions have recently been described including control of necroptosis and inflammasome activity. In this review, we discuss the function of the A20/TNFAIP3 enzyme and its critical role in various innate and adaptive immune cells. Finally, we discuss the latest findings on SNPs in human autoinflammatory and autoimmune diseases and address that genotyping of SNPs may guide treatment decisions.

Promoting education in rural areas and combating school dropout remain critical challenges for Morocco's education sector. In this context, this study aims to evaluate the impact of the school canteen program on student enrolment and efforts to mitigate school dropout in rural schools. The analysis is based on data from a national social support survey conducted by the National Human Development Observatory (ONDH) in 2018, involving a representative sample of 3,039 rural and urban households. Employing a micro-econometric approach, specifically the propensity score matching (PSM) method, the findings reveal a significant effect of school canteens in reducing repetition rates among rural students. However, the study did not find conclusive evidence of a positive impact on enrolment rates for these students. Additionally, the evaluation explores the integration of this program, assesses its targeting strategy, and highlights critical factors for achieving a high-performing education sector that emphasizes both accessibility and quality.

A20 haploinsufficiency (HA20) is an autoinflammatory disease caused by heterozygous loss-of-function variations in TNFAIP3 , the gene encoding the A20 protein. Diagnosis of HA20 is challenging due to its heterogeneous clinical presentation and the lack of pathognomonic symptoms. While the pathogenic effect of TNFAIP3 truncating variations is clearly established, that of missense variations is difficult to determine. Herein, we identified a novel TNFAIP3 variation, p.(Leu236Pro), located in the A20 ovarian tumor (OTU) domain and demonstrated its pathogenicity. In the patients’ primary cells, we observed reduced A20 levels. Protein destabilization was predicted in silico for A20_Leu236Pro and enhanced proteasomal degradation was confirmed in vitro through a flow cytometry-based functional assay. By applying this approach to the study of another missense variant, A20_Leu275Pro, for which no functional characterization has been performed to date, we showed that this variant also undergoes enhanced proteasomal degradation. Moreover, we showed a disrupted ability of A20_Leu236Pro to inhibit the NF-κB pathway and to deubiquitinate its substrate TRAF6. Structural modeling revealed that two residues involved in OTU pathogenic missense variations (i.e. Glu192Lys and Cys243Tyr) establish common interactions with Leu236. Interpretation of newly identified missense variations is challenging, requiring, as illustrated here, functional demonstration of their pathogenicity. Together with functional studies, in silico structure analysis is a valuable approach that allowed us (i) to provide a mechanistic explanation for the haploinsufficiency resulting from missense variations and (ii) to unveil a region within the OTU domain critical for A20 function.

A20, encoded by TNFAIP3, is a critical negative regulator of immune activation. A20 is a ubiquitin editing enzyme with multiple domains, each of which mediates or stabilizes a key ubiquitin modification. A20 targets diverse proteins that are involved in pleiotropic immunologic pathways. The complexity of A20-mediated immunomodulation is illustrated by the varied effects of A20 deletion in different cell types and disease models. Clinically, the importance of A20 is highlighted by its extensive associations with human disease. A20 germline variants are associated with a wide range of inflammatory diseases, while somatic mutations promote development of B cell lymphomas. More recently, the discovery of A20 haploinsufficiency (HA20) has provided real world evidence for the role of A20 in immune cell function. Originally described as an autosomal dominant form of Behcet’s disease, HA20 is now considered a complex inborn error of immunity with a broad spectrum of immunologic and clinical phenotypes.

Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.

The M1 polarization of microglia and neuroinflammation restrict the treatment of acute spinal cord injury (ASCI), and long non‐coding ribonucleic acid (lncRNA) maternally expressed gene 3 (MEG3) expression is lessened in ASCI. However, the function and mechanism of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI are unclear. The expressions of lncRNA MEG3 in ASCI mouse spinal cord tissues and lipopolysaccharide (LPS)‐treated primary microglia and BV2 cells were quantified through a quantitative real‐time polymerase chain reaction. In‐vitro assays were conducted to explore the function of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI. RNA degradation, RNA immunoprecipitation, RNA pull‐down, cycloheximide‐chase, and ubiquitination analyses were carried out to probe into the mechanism of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI. The lncRNA MEG3 expression was lessened in the ASCI mouse spinal cord tissues and LPS‐treated primary microglia and BV2 cells, and the overexpression of lncRNA MEG3 restrained the M1 polarization of microglia and the neuroinflammation by regulating the NF‐κB signaling pathway. For the investigation of the potential mechanism of such, the overexpression of lncRNA MEG3 restrained the M1 polarization of microglia through the HuR/A20/NF‐κB axis and boosted the motor function recovery and neuroinflammation relief in the mice with SCI. The overexpression of lncRNA MEG3 restrained the M1 polarization of microglia through the HuR/A20/NF‐κB axis. A working model was used to reveal the underlying mechanism of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation.

The NF-κB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-KB is achieved by K63-1inked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the IKB kinase （IKK）. Ubiquitination is a highly dynamic process and is balanced by deubiquitinases that cleave polyubiquitin chains and terminate downstream signaling events. The A20 deubiquitinase is a critical negative regulator of NF-κB and inflammation, since A20-deficient mice develop uncontrolled and spontaneous multi-organ inflammation. Furthermore, specific polymorphisms in the A20 genomic locus predispose humans to autoimmune disease. Recent studies also indicate that A20 is an important tumor suppressor that is inactivated in B-cell lymphomas. Therefore, targeting A20 may form the basis of novel therapies for autoimmune disease and lymphomas.

BackgroundA20 is an anti-inflammatory molecule in nucleus pulposus (NP) cells. The anti-inflammatory properties of A20 are mainly attributed to its ability to suppress the NF-κB pathway. However, A20 can protect cells from death independently of NF-κB regulation. This study aimed to investigate the effects of A20 on pyroptosis and apoptosis of NP cells induced by lipopolysaccharide (LPS).MethodsNP cells induced by LPS were used as an in vitro model of the inflammatory environment of the intervertebral disc. Pyroptosis, apoptosis, and mitophagy marker proteins were detected. Then, NP cells were transfected with A20 overexpressed lentivirus or A20-siRNA. Annexin V FITC/PI, Western blotting, and immunofluorescence assays were used to detect the apoptosis, pyroptosis, and mitophagy of NP cells. Furthermore, the expressions of A20, related proteins, and related inflammatory cytokines were detected by western blotting, and ELISA.ResultsApoptosis and pyroptosis of NP cells increased gradually treated with LPS for 12 h, 24 h, and 48 h. Differently, the level of mitophagy increased first and then decreased, and was the highest at LPS treatment for 12 h. Overexpression or knockdown of A20 in NP cells revealed that A20 attenuated the pyroptosis, apoptosis, and production of inflammatory cytokines of NP cells induced by LPS, while A20 sponsored mitophagy, reduced ROS production and collapse of mitochondrial membrane potential (ΔΨm). Moreover, A20 also promoted mitochondrial dynamic homeostasis and attenuated LPS-induced excessive mitochondrial fission. Excitingly, inhibition of mitophagy attenuated the effect of A20 on the negative regulation of pyroptosis of NP cells induced by LPS. Pyroptosis was accompanied by a large release of inflammatory cytokines. Inhibition of pyroptosis also significantly reduced apoptosis of NP cells. Finally, The mitochondria-targeted active peptide SS-31 inhibited LPS-induced pyroptosis and ROS production in NP cells.ConclusionsTo sum up, A20 attenuates pyroptosis and apoptosis of NP cells via promoting mitophagy and stabilizing mitochondrial dynamics. Besides, A20 reduces LPS-induced NP cell apoptosis by inhibiting NLRP3 inflammasome-mediated pyroptosis. It provides theoretical support for the reduction of functional NP cell loss in the intervertebral disc through the gene-targeted intervention of A20.

Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in which encodes A20 protein. mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20. We reviewed the HA20 cases in previous literature and summarized the clinical features, mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption. A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups ( = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group ( = 0.002 and = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD ( = 0.006 and < 0.001, respectively). HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders.