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CAVD (calcific aortic valve disease) involves an inflammatory response similar to pyroptosis; therefore, we speculated that the progression of pyroptosis might be involved in the pathogenesis of CAVD.We first investigated the expression of pyroptosis related genes in human CAVD, non-CAVD control and AS (calcific aortic stenosis) tissues. We further confirmed these genes by using CAVD cell and mouse models. Finally, we explored the functional molecular mechanism in the cell model.Our recent studies found that miR-29b plays an important role in CAVD, and we wanted to further address whether miR-29b is a key factor in the progression of pyroptosis related to CAVD. In this study, we found NLRP3 was highly expressed in CAVD patients and models. In contrast, SOCS1, a suppressor of NLRP3, showed reduced expression in CAVD. Furthermore, we found that ASC, Caspase-1, IL-1β, Cleaved IL-18 and p-JAK2 were all upregulated in the tissues of CAVD patients, suggesting the likelihood of activation of the inflammasome. Then, we found that miR-29b participated in the NLRP3-regulated CAVD pathway through its target gene STAT3 (signal transducer and activator of transcription 3). Finally, we found that a miR-29b inhibitor could mitigate the increases in osteogenic differentiation and pyroptosis and that SOCS1 showed negative regulation of osteogenic differentiation and pyroptosis in CAVD.These findings suggested NLRP3 inflammasome-related genes are highly expressed in CAVD, and miR-29b reverses osteoblastic differentiation of aortic valve interstitial cells by regulating pyroptosis and inhibiting inflammation via the STAT3/SOCS1 pathway.

Wogonoside (WG) is a flavonoid chemical component extracted from Scutellaria baicalensis, which exerts therapeutic effects on liver diseases. Ferroptosis, a novel form of programmed cell death, regulates diverse physiological/pathological processes. In this study, we attempted to investigate a novel mechanism by which WG mitigates liver fibrosis by inducing ferroptosis in hepatic stellate cells (HSCs). A CCl

Hepatic ischemia-reperfusion (I/R) injury is the main factor affecting the morbidity and mortality associated with perioperative complications of liver transplantation and major hepatectomy. AXL is a member of the TYRO3, AXL, MERTK family and is involved in immune and apoptosis processes in multiple organs. However, the role of AXL in hepatic I/R injury remains to be elucidated.Mice pretreated with rmGas6 or R428 and mice tail vein injected with adeno-associated virus knockdown suppressor of cytokine signaling protein-1 (SOCS-1) underwent liver I/R surgery to detect the function of activated AXL in vivo. Primary hepatocytes undergo hypoxic reoxygenation injury in vitro.AXL expression was significantly upregulated, and phosphorylated-AXL was substantially downregulated in liver transplantation patients and hepatic I/R surgery mice. A mouse model of hepatic I/R injury showed that AXL activation reduced liver inflammation and liver cells apoptosis. The inhibition of AXL activation (AXL-specific inhibitor R428) aggravated hepatic I/R injury, resulted in larger areas of liver injury, aggravated inflammatory response, and increased apoptosis of liver cells. In addition, activated AXL promotes the expression level of SOCS-1 and inhibits toll-like receptor 4 and its downstream signaling pathways. Finally, SOCS-1 was knocked down with an adeno-associated virus, and activated AXL failed to protect against hepatic I/R injury.AXL activation protects the liver from I/R injury by upregulating SOCS-1 and inhibiting the toll-like receptor 4/myeloid differentiation factor-88/nuclear factor kappa-B signaling axis. Targeting AXL may be a new therapeutic option for ameliorating hepatic I/R injury.

Febrile neutropenia (FEN) was reported in patients with solid malignancies at a rate of 5-10% and in patients with hematological malignancies at a rate of 20-25%. In our study, we aimed to investigate the effects of mannose-binding lectin 2 (MBL2) (rs1800450) and suppressor of cytokine signaling-1 (SOCS1) (rs33989964) gene variants on patients with FEN.A total of 123 patients who applied to pediatric emergency department between December 2019-12/2020 included in the study. Thirteen patients were excluded from the study due to the inability to obtain DNA. Demographic-clinical features at initial diagnosis and genotype distributions were recorded. The control group consisted of volunteers with the same ethnicity, age and gender, no active infection, and no consanguinity.CA/CA genotype of SOCS1 was found to be significantly higher in the healthy control group (p = 0.028). AB/BB genotype of MBL2 was significantly higher in FEN patients with a MASCC score of high risk, AA genotype was found to be higher in patients with low risk (p = 0.001). While the rate of microbiologically documented infection (MDI) was significantly lower in patients with the AA genotype of MBL2, it was significantly higher in patients with AA/BB genotypes (p = 0.025). MDI rate in patients with the del/del genotype of SOCS1 was found to be significantly lower than in patients with CA/CA + CA/del genotypes (p = 0.026).In this study, it was revealed that low expression-related MBL2 genotypes were riskier for FEN and also, gene variants associated with high SOCS1 transcription were both protective against FEN and increased the rate of culture-negativity.

Inflammation is a key player in the regulation of depression. Shanzhiside methylester (SM) is an iridoid glycoside with strong anti-inflammatory properties. However, the antidepressant effect of SM remains unknown. The present study aimed to investigate whether SM protects against depression by targeting inflammation. A chronic unpredictable mild stress (CUMS)-induced mouse model of depression was established to assess the antidepressant effect of SM in vivo. In addition, an LPS plus ATP-induced cellular model of inflammation was used to explore the related inflammatory mechanism. We found that both SM and miRNA-155-5p sponge markedly remedied CUMS-induced depression-like behaviors in the sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST), accompanied by decreased Iba1 expression and the production of TNF-α, IL-1β, and IL-6. Moreover, SM and miRNA-155-5p sponge upregulated the protein levels of SOCS1 and downregulated the protein expression of p-JAK2 and p-STAT3 in the hippocampus of CUMS-exposed mice. miRNA-155-5p expression was also decreased following SM and miRNA-155-5p sponge administration. Furthermore, SM repressed LPS- and ATP-induced inflammatory responses in BV2 cells by regulating the SOCS1/JAK2/STAT3 signaling pathway, which was similar to the anti-inflammatory effects induced by the miRNA-155-5p sponge. Collectively, these findings suggested that SM exerted antidepressant actions by targeting the miRNA-155-5p/SOCS1 axis.

Suppressor of cytokine signaling 1 (SOCS1) has emerged as a potential therapeutic target in inflammatory and viral diseases. SOCS1 operates via its kinase inhibitory region, Src homology 2 (SH2) domain, and SOCS box to negatively regulate the Janus kinase/signal transducers and activators of transcription signaling pathway. In this study, we utilized native phosphotyrosine peptide substrates as a starting point to iteratively explore the requirement of each amino acid position to target the SH2 domain of SOCS1. We show that Met, Thr, Thr, Val, and Asp in the respective -1, +1, +2, +3, and +5 positions within the peptide substrate are favored for binding to the SOCS1-SH2 domain and identifying several phosphotyrosine peptides that have potent SOCS1 binding affinity with IC

Constitutive activation of STAT3 promotes oncogenesis and growth of oral squamous cell carcinoma (OSCC). We investigated the mechanism of action of suppressor of cytokine signaling 1 (SOCS1), an endogenous inhibitor of JAK, as gene therapy for OSCC.Antitumor effect of SOCS1 was compared to JAK inhibitor I by cell proliferation assay, cell cycle analysis, and apoptosis analysis in vitro. In addition, antitumor effect was evaluated using xenograft mouse models in vivo.JAK inhibitor I inhibited the proliferation of KOSC2 cl3-43 or T3M-1 clone2 OSCC cell lines in vitro. While JAK inhibitor I arrested both cell lines at the G2/M phase, induction of apoptosis was observed in T3M-1 clone2 cells, but not KOSC2-cl3-43 cells. An adenoviral vector expressing SOCS1 (AdSOCS1) significantly decreased the proliferation of both OSCC cell lines and induced G2/M phase cell cycle arrest and apoptosis, suggesting that induction of apoptosis of KOSC2 cl3-43 cells by AdSOCS1 is regulated by the JAK/STAT independent pathway. Overexpression of SOCS1 inhibited activation of the JAK/STAT and p44/42 MAPK pathways, while JAK inhibitor I inhibited activation of the JAK/STAT pathway only. Consistently, expression of Mcl-1 was decreased by overexpression of SOCS1, but not JAK inhibitor I. Additionally, KOSC2 cl3-43 or T3M-1 clone2 OSCC cells were subcutaneously implanted in the flanks of two xenograft mouse models. As compared to a control adenovirus vector (AdLacZ), intratumor injection of AdSOCS1 significantly decreased the tumor volume and induced apoptosis in vivo.SOCS1 gene therapy may be a beneficial approach for the treatment of OSCC.

Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation is initiated by mutations in the JAK2 gene. This activation is in turn, a vital pathogenetic mechanism in myeloproliferative neoplasms (MPNs). However, several factors affect the pathogenesis of MPNs other than the JAK2 gene mutations, such as the downregulation of cytokine signaling (SOCS) proteins, which are potent inhibitors of the JAK/STAT pathway. Therefore, we hypothesized that the regulation of SOCS protein system might be a possible pathogenetic mechanism of MPNs through activating the JAK/STAT pathway.Our study aimed to investigate the status of the Suppressors of cytokine signaling 1 (SOCS1) in 125 MPNs specimens at the level of mutated points. The acquired mutations, aberrant expression, and/or CpG island hypermethylation of SOCS1 were analyzed among Philadelphia-negative myeloproliferative neoplasm patients.SOCS1 was identified in 20.0% of all patients with Philadelphia-negative myeloproliferative neoplasm. At the diagnosis, the prevalence of methylation was 41.0% for Polycythaemia Vera (PV), 27.7% for Essential Thrombocythaemia (ET), and 6.6% for Primary Myelofibrosis (PMF). The methylation was not detected in 20 healthy adult people. A significant association was found between disease groups (p=.077). The presence of methylated SOCS1 was found to be significantly correlated with age (p=.005), total RBCs count (p=.019), hemoglobin (Hb) concentration (p=.002), and Hematopoietic cell transplant (HCT) (p=.007) in PV patients. However, the presence of methylated SOCS1 was found to be significantly associated with age (p=.012), total RBCs count (p=.022), Hb concentration (p=.024), HCT (p=.033), and platelets count (p=.037) in ET patients. Moreover, the presence of methylated SOCS1 was significantly associated with Hb concentration (p=.046) and HCT (p=.040) in PMF patients.We concluded that the activation of the JAK/STAT signaling pathway in alternative or with JAK2 mutations leads to SOCS1 hypermethylation, which could represent a potential therapeutic target.

Age-related disorders, such as Alzheimer’s disease (AD) and age-related macular degeneration (AMD) share common features such as amyloid-β (Aβ) protein accumulation. Retinal deposition of Aβ aggregates in AMD patients has suggested a potential link between AMD and AD. In the present study, we analyzed the expression pattern of a focused set of miRNAs, previously found to be involved in both AD and AMD, in the retina of a triple transgenic mouse model of AD (3xTg-AD) at different time-points. Several miRNAs were differentially expressed in the retina of 3xTg-AD mice, compared to the retina of age-matched wild-type (WT) mice. In particular, bioinformatic analysis revealed that miR-155 had a central role in miRNA-gene network stability, regulating several pathways, including apoptotic and inflammatory signaling pathways modulated by TNF-related apoptosis-inducing ligand (TNFSF10). We showed that chronic treatment of 3xTg-AD mice with an anti-TNFSF10 monoclonal antibody was able to inhibit the retinal expression of miR-155, which inversely correlated with the expression of its molecular target SOCS-1. Moreover, the fine-tuned mechanism related to TNFSF10 immunoneutralization was tightly linked to modulation of TNFSF10 itself and its death receptor TNFRSF10B, along with cytokine production by microglia, reactive gliosis, and specific AD-related neuropathological hallmarks (i.e., Aβ deposition and Tau phosphorylation) in the retina of 3xTg-AD mice. In conclusion, immunoneutralization of TNFSF10 significantly preserved the retinal tissue in 3xTg-AD mice, suggesting its potential therapeutic application in retinal degenerative disorders.

Cerebral ischemia results in loss of cerebral blood flow, which contributes to neuronal damage, neurocognitive impairment, as well as learning and memory difficulties. Although reperfusion is necessary to restore the blood supply to the brain, it also leads to several detrimental effects on the brain. The purpose of this study was to assess the effects of ulinastatin (UTI) on preventing focal cerebral ischemia/reperfusion-induced injury (FCIRI). First, a rat model of FCIRI was established and treated with UTI. The effects of UTI on FCIRI in rats were evaluated using Morris water maze assay, triphenyl tetrazolium chloride staining, TUNEL, western blot assay, and enzyme-linked immunosorbent assay analysis. UTI was found to improve the learning memory ability, reduce infarction area, inhibit apoptosis and decrease inflammation in FCIRI rats. Messenger RNA microarray analysis of hippocampal tissues revealed that suppressor of cytokine signalling-1 (SOCS1) was the downstream target of UTI in FCIRI. SOCS1 depletion impaired the protective effect of UTI on FCIRI in rats. SOCS1 blocked the activation of the JAK2/STAT3 pathway. JAK2 inhibitor caused the JAK2/STAT3 pathway deficit, hence reversing the effect of sh-SOCS1 on FCIRI in rats. Taken together, our results demonstrate that UTI alleviated FCIRI in rats, which was, to some extent, related to SOCS1-mediated JAK2/STAT3 pathway.

Duck Tembusu virus (DTMUV) is an emerging pathogenic flavivirus that mainly causes a decrease in egg production in infected waterfowl. Similar to other members of the Flaviviridae family, it can proliferate in most mammalian cells and may also pose a potential threat to nonavian animals. In previous studies, we found that DTMUV infection can upregulate suppressor of cytokine signaling 1 (SOCS1) to inhibit type I interferon (IFN) production and promote virus replication, but the specific mechanism is unclear. Furthermore, little is known about the regulatory role of ubiquitination during flavivirus infection. In this study, we found that activation of Toll-like receptor 3 (TLR3) signaling rather than type I IFN stimulation led to the upregulation of SOCS1 during DTMUV infection. Further studies revealed that JOSD1 stabilized SOCS1 expression by binding to the SH2 domain of SOCS1 and mediating its deubiquitination. In addition, JOSD1 also inhibited type I IFN production through SOCS1. Finally, SOCS1 acts as an E3 ubiquitin ligase that binds to IFN regulatory factor 7 (IRF7) through its SH2 domain and mediates K48-linked ubiquitination and proteasomal degradation of IRF7, ultimately inhibiting type I IFN production mediated by IRF7 and promoting viral proliferation. These results will enrich and deepen our understanding of the mechanism by which DTMUV antagonizes the host interferon system. IMPORTANCE DTMUV is a newly discovered flavivirus that seriously harms the poultry industry. In recent years, there have been numerous studies on the involvement of ubiquitination in the regulation of innate immunity. However, little is known about the involvement of ubiquitination in the regulation of flavivirus-induced type I IFN signaling. In this study, we found that SOCS1 was induced by TLR3 signaling during DTMUV infection. Furthermore, we found for the first time that duck SOCS1 protein was also modified by K48-linked polyubiquitination, whereas our previous study found that SOCS1 was upregulated during DTMUV infection. Further studies showed that JOSD1 stabilized SOCS1 expression by mediating the deubiquitination of SOCS1. While SOCS1 acts as a negative regulator of cytokines, we found that DTMUV utilized SOCS1 to mediate the ubiquitination and proteasomal degradation of IRF7 and ultimately inhibit type I IFN production, thereby promoting its proliferation.

Acute lung injury (ALI) is a serious clinical pulmonary disease. The pathogenesis of ALI is related to the excessive release of inflammatory factors and upregulation of mucin 5AC (MUC5AC). Telmisartan is a novel antihypertension agent that exerts promising anti-inflammatory effects. The purpose of this study is to investigate whether Telmisartan has a protective role in lipopolysaccharide (LPS)-induced MUC5AC expression and to explore the underlying mechanism in human bronchial epithelial cells. Firstly, the decreased cell viability, elevated release of lactate dehydrogenase (LDH), and excessively released inflammatory factors tumor necrosis factor-α (TNF-α), interleukin- 6 (IL-6), and transforming growth factor-β (TGF)-β in bronchial BEAS-2B epithelial cells induced by stimulation with LPS were significantly reversed by the introduction of Telmisartan. Secondly, the upregulated MUC5AC and downregulated suppressor of cytokine signaling 1 (SOCS1) caused by stimulation with LPS were dramatically reversed by Telmisartan. Notably, treatment with Telmisartan attenuated LPS-induced activation of nuclear factor κ-B (NF-κB). Lastly, silencing of SOCS1 abolished the protective effects of Telmisartan against LPS-induced production of MUC5AC and the activation of NF-κB. Based on these findings, we conclude that Telmisartan displayed a protective effect against LPS by improving mitochondrial function, mitigating inflammatory response, and reducing the production of mucin 5AC by regulating the SOCS1/NF-κB axis in human bronchial epithelial cells., Graphical abstract

Although microRNA-155 (miR-155) is considered a pro-inflammatory mediator, cumulative evidence indicates that it also has anti-inflammatory effects in macrophages and dendritic cells. In this study, we identified the dramatic expression changes of more than half of potential miR-155-targeted genes upon lipopolysaccharide (LPS) stimulation; 223 genes were down-regulated and 85 genes were up-regulated, including suppressor of cytokine signaling 1 (SOCS1) and transforming growth factor-β-activated kinase 1-binding protein 2 (TAB2), two well-known genes involved in miR-155-mediated regulation of the Toll-like receptor 4 (TLR4) signaling pathway. We also found that miR-155 acted as an anti-inflammatory mediator in the initial stage of LPS-induced inflammatory response mainly through repressing TAB2 protein translation, and as a pro-inflammatory mediator by down-regulating SOCS1 in the later stage. Meanwhile, overexpression of TAB2 3' untranslated region (UTR) in macrophages promoted the development of endotoxin tolerance by competing for binding with miR-155, which resulted in an elevated expression level of SOCS1 protein. These findings provide new insights for understanding the regulatory mechanisms in fine-tuning of LPS-induced innate immune response.

Ulcerative colitis is characterized by relapsing inflammation in the gastrointestinal tract with limited treatment options. The aim of the present study was to assess the anti-inflammatory effect of Suppressor of cytokine signaling (SOCS1) on lipopolysac- charide-stimulated RAW264.7 cells and to investigate its potential mechanisms.The in vitro ulcerative colitis model was established by using lipopolysaccharide-stimulated RAW264.7 cells. Western blot- ting was used to detect the protein expression levels of SOCS1, JAK2, STAT3, and VDR. Reverse transcription-quantitative polymerase chain reaction was used to measure the mRNA expression of SOCS1, miR-222-3p, and VDR. An enzyme-linked immunosorbent assay was performed to measure the levels of inflammatory cytokines. A luciferase assay assessed the binding of SOCS1 to miR-222-3p. A total of 15 patients with ulcerative colitis and 18 healthy controls were recruited. The expression levels of SOCS1 and miR-222-3p in the colonic mucosa tissues of patients with ulcerative colitis and healthy controls were determined by reverse transcription-quantitative polymerase chain reaction.SOCS1 upregulation inhibited the lipopolysaccharide-induced inflammation in RAW264.7 cells. SOCS1 was confirmed to be tar- geted by miR-222-3p. Silencing SOCS1 significantly abolished the inhibitory effects of miR-222-3p downregulation on inflammation. MiR-222-3p activated STAT3 signaling and reduced VDR expression by targeting SOCS1 in lipopolysaccharide-treated RAW264.7 cells. Additionally, miR-222-3p expression was upregulated in ulcerative colitis patients (P = 5.16E-10), while SOCS1 (P = 2.75E-10) and VDR (P = 52.5E-9) expression was downregulated in ulcerative colitis patients. Endoscopic scores (UCEIS) revealed significant positive cor- relation with miR-222-3p and negative correlation with SOCS1 and VDR.MiR-222-3p targets SOCS1 to aggravate the inflammatory response by suppressing VDR and activating STAT3 signaling in ulcerative colitis.

In order to investigate the expression of Suppressor of Cytokine Signaling 1 (SOCS1) and its regulatory mechanism by mir-150 in a lipopolysaccharide (LPS) tolerant mouse model of endotoxin, a total of 60 male BALB/C mice were randomly divided into 2 groups. The LPS is used to construct the endotoxin resistant mouse model and the mice are included in the model group (n = 30), 0.9% sodium chloride injection is used to construct the normal control group (n = 30). And tumor necrosis factor-α (TNF-α) is determined by Elisa to determine whether the model was successfully constructed. The correlation between SOCS1 protein and mir-150 is analyzed by the Pearson correlation coefficient. In the experiments, the results show that the expression of TNF-α in the macrophage fluid of the model group is significantly decreased ( P < 0.05 ), indicating that the endotoxin tolerance mouse model is successfully constructed, so the secretion of TNF-α is reduced.

Introduction SOCS1, a negative regulator of JAK/STAT signaling, is among the most frequently mutated genes in DLBCL and classical Hodgkin lymphoma. The C-terminal SOCS box domain, mediating the degradation of phospho-JAK2, is often affected or even lacking. The analysis of such variants is hampered by the lack of a SOCS1-specific monoclonal antibody recognizing the C-terminus of SOCS1. As this C-terminus is often lost or mutated in B-cell lymphomas, staining with amino-terminal targeting antibodies in a lymphoma setting might be misleading. Methods BALB/c mice were immunized with a truncated SOCS1 C-terminal protein. The supernatant of generated hybridoma cells was screened by ELISA and, immunohistochemically, on formalin-fixed and paraffin-embedded tonsil. After antibody purification by affinity chromatography, epitope mapping and cross-reactivity check followed via substitution scans. SOCS1 protein expression was investigated on cell cultures and cytoblocks of SOCS1WT stably transfected HEK293T cells, lymphoma cell lines and lymphoid tissues. Results Procedures resulted in one monoclonal IgG1 anti-SOCS1 antibody, 424C, that recognizes and strongly binds to the C-terminal region of SOCS1 in immunoblot and immunohistochemistry analyses. Conclusion This new anti-SOCS1 monoclonal antibody is a valuable tool to detect SOCS1 expression dependent on an existing SOCS1 box and, therefore, indicating a full-length SOCS1 protein.

Viral myocarditis (VMC) is a life-threatening disease characterized by severe cardiac inflammation generally caused by coxsackievirus B3 (CVB3) infection. Several microRNAs (miRNAs or miRs) are known to play crucial roles in the pathogenesis of VMC. The study aimed to decipher the role of miR-30a-5p in the underlying mechanisms of VMC pathogenesis. We first quantified miR-30a-5p expression in a CVB3-induced mouse VMC model. The physiological characteristics of mouse cardiac tissues were then detected by hematoxylin and eosin (HE) and Picrosirius red staining. We established the correlation between miR-30a-5p and SOCS1, using dual-luciferase gene assay and Pearson's correlation coefficient. The expression of inflammatory factors (IFN-γ, IL-6, IL-10, and IL-13), M1 polarization markers [TNF-α, inducible nitric oxide synthase (iNOS)], M2 polarization markers (Arg-1, IL-10), and myocardial hypertrophy markers [atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)] was detected by RT-qPCR and Western blot analysis. miR-30a-5p was found to be highly expressed in VMC mice. Silencing of miR-30a-5p improved the cardiac function index and reduced heart weight-to-body weight ratio, myocardial tissue pathological changes and fibrosis degree, serological indexes, as well as proinflammatory factor levels, while enhancing anti-inflammatory factor levels in VMC mice. Furthermore, silencing of miR-30a-5p inhibited M1 polarization of macrophages while promoting M2 polarization in vivo and in vitro. SOCS1 was a target gene of miR-30a-5p, and the aforementioned cardioprotective effects of miR-30a-5p silencing were reversed upon silencing of SOCS1. Overall, this study shows that silencing of miR-30a-5p may promote M2 polarization of macrophages and improve cardiac injury following VMC via SOCS1 upregulation, constituting a potential therapeutic target for VMC treatment.

Suppressor of Cytokine Signaling 1 (SOCS1) functions as a tumor suppressor in hepatocellular carcinoma and many other types of cancers. SOCS1 mediates its functions by inhibiting tyrosine kinases, promoting ubiquitination and proteasomal degradation of signal transducing proteins, and by modulating transcription factors. Here, we studied the impact of SOCS1 on the hepatocyte proteome using Stable Isotopic Labelling of Amino acids in Cell culture (SILAC)-based mass spectrometry on the Hepa1-6 murine HCC cell line stably expressing wildtype SOCS1 or a mutant SOCS1 with impaired SH2 domain. As SOCS1 regulates the hepatocyte growth factor (HGF) receptor, the MET receptor tyrosine kinase (RTK), the SILAC-labelled cells were stimulated or not with HGF. Following mass spectrometry analysis, differentially modulated proteins were identified, quantified and analyzed for pathway enrichment. Of the 3440 proteins identified in Hepa-SOCS1 cells at steady state, 181 proteins were significantly modulated compared to control cells. The SH2 domain mutation and HGF increased the number of differentially modulated proteins. Protein interaction network analysis revealed enrichment of SOCS1-modulated proteins within multiprotein complexes such as ubiquitin conjugating enzymes, proteasome, mRNA spliceosome, mRNA exosome and mitochondrial ribosome. Notably, the expression of UBE2D ubiquitin conjugating enzyme, which is implicated in the control of growth factor receptor tyrosine kinase signaling, was found to be regulated by SOCS1. These findings suggest that SOCS1, induced by cytokines, growth factors and diverse other stimuli, has the potential to dynamically modulate of large macromolecular regulatory complexes to help maintain cellular homeostasis.

Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

Bladder cancer (BCa) is a common carcinoma of the urinary tract, which occurs in the bladder mucosa. In recent years, people have recognized that epigenetic changes such as DNA methylation play important roles in the development of BCa but the specific mechanism is unclear. In this study, we detected the methylation rates in the SOCS1 gene of 490 subjects (including 247 patients with BCa and 243 healthy controls) using the MassARRAY EpiTYPER system. Principal component analysis (PCA) was conducted with the aim of identifying common underlying patterns that could explain the largest part of common variance in methylation across units. A logistic regression model was used to assess the relation of SOCS1 methylation patterns with factors related to BCa risk. The methylation rates varied for different CpG units and were significantly different in BCa patients compared to controls. Six principal component factors were extracted by combining initial eigenvalue, explanatory power, and Scree Plot. After adjusting for age, gender, family history of bladder cancer, smoking, and drinking, we observed that Factor 1 (OR=0.051, 95% CI: 0.015-0.178, p

Background: Spectrin, beta, non-erythrocytic 1 (SPTBN1), an adapter protein for transforming growth factor beta (TGF-β) signaling, is recognized as a tumor suppressor in the development of hepatocellular carcinoma (HCC); however, the underlying molecular mechanisms of this tumor suppression remain obscure. Methods: The effects on expression of pro-inflammatory cytokines upon the inhibition or impairment of SPTBN1 in HCC cell lines and liver tissues of Sptbn1+/- and wild-type (WT) mice were assessed by analyses of quantitative real-time reverse-transcription polymerase chain reaction (QRT-PCR), enzyme linked immunosorbent assay (ELISA), Western blotting and gene array databases from HCC patients. We investigated the detailed molecular mechanisms underlying the inflammatory responses by immunoprecipitation-Western blotting, luciferase reporter assay, chromatin immunoprecipitation quantitative real time PCR (ChIP-qPCR), immunohistochemistry (IHC) and electrophoretic mobility shift assay (EMSA). The proportion of myeloid-derived suppressor cells in liver, spleen, bone marrow and peripheral blood samples from WT and Sptbn1+/- mice were measured by fluorescence-activated cell sorting (FACS) analysis. Further, the hepatocacinogenesis and its correlation with inflammatory microenvironment by loss of SPTBN1/SOCS1 and induction of p65 were analyzed by treating WT and Sptbn1+/- mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Results: Loss of SPTBN1 in HCC cells upregulated the expression of pro-inflammatory cytokines including interleukin-1α (IL-1α), IL-1β, and IL-6, and enhanced NF-κB transcriptional activation. Mechanistic analyses revealed that knockdown of SPTBN1 by siRNA downregulated the expression of suppressor of cytokine signaling 1 (SOCS1), an E3 ligase of p65, and subsequently upregulated p65 accumulation in the nucleus of HCC cells. Restoration of SOCS1 abrogated this SPTBN1 loss-associated elevation of p65 in HCC cells. In human HCC tissues, SPTBN1 gene expression was inversely correlated with gene expression of IL-1α, IL-1β and IL-6. Furthermore, a decrease in the levels of SPTBN1 gene, as well as an increase in the gene expression of IL-1β or IL-6 predicted shorter relapse free survival in HCC patients, and that HCC patients with low expression of SPTBN1 or SOCS1 protein is associated with poor survival. Heterozygous loss of SPTBN1 (Sptbn1+/- ) in mice markedly upregulated hepatic expression of IL-1α, IL-1β and IL-6, and elevated the proportion of myeloid-derived suppressor cells (MDSCs) and CD4+CD25+Foxp3+ regulatory T cells (Foxp3+Treg) cells in the liver, promoting hepatocarcinogenesis of mouse fed by DDC. Conclusions: Our findings provided evidence that loss of SPTBN1 in HCC cells increases p65 protein stability via the inhibition of SOCS1 and enhances NF-κB activation, stimulating the release of inflammatory cytokines, which are critical molecular mechanisms for the loss of SPTBN1-induced liver cancer formation. Reduced SPTBN1 and SOCS1 predict poor outcome in HCC patients.

BACKGROUND Ferroptosis involves in the development and therapeutic response of various types of tumors. This study aims to explore ferroptosis-related prognostic genes that could further accurately stratify AML patients. METHODS We investigated the prognosis significance of ferroptosis-related genes in AML by Univariate and multivariate Cox proportional hazards regression analyses. With the methylation data of TCGA samples, we looked for methylation sites associated with prognostic genes and compared the correlation between methylation and mRNA expression. R software and 'edgeR' packages were used to identify the DEGs between the high-and-low-risk groups divided by the FRPGs prognosis model and then run GO enrichment, KEGG pathway, and PPI network. RESULTS We found a prognostic risk model that included AKR1C2 and SOCS1 predicted outcomes in AML patients. Methylation analysis showed that AKR1C2 and SOCS1 are negatively regulated by their methylation, leading to their low expression in AML patients. Besides, both decreased SOCS1 expression and hypermethylation predicted favorable OS and PFS in AML patients. Finally, this prognostic risk model exhibited a close correlation with several clinical features, especially with age (P=0.005), cytogenetic type (P=0.031), risk_cytogenetic (P=0.001), and risk_molecular (P

Suppressors of cytokine signaling (SOCS) exhibit diverse antiinflammatory effects. Since ROS acts as a critical mediator of inflammation, we have investigated the anti-inflammatory mechanisms of SOCS via ROS regulation in monocytic/macrophagic cells. Using PMA-differentiated monocytic cell lines and primary BMDMs transduced with SOCS1 or shSOCS1, the LPS/TLR4-induced inflammatory signaling was investigated by analyzing the levels of intracellular ROS, antioxidant factors, inflammasome activation, and pro-inflammatory cytokines. The levels of LPS-induced ROS and the production of pro-inflammatory cytokines were notably down-regulated by SOCS1 and up-regulated by shSOCS1 in an NAC-sensitive manner. SOCS1 up-regulated an ROS-scavenging protein, thioredoxin, via enhanced expression and binding of NRF-2 to the thioredoxin promoter. SOCS3 exhibited similar effects on NRF-2/thioredoxin induction, and ROS downregulation, resulting in the suppression of inflammatory cytokines. Notably thioredoxin ablation promoted NLRP3 inflammasome activation and restored the SOCS1-mediated inhibition of ROS and cytokine synthesis induced by LPS. The results demonstrate that the anti-inflammatory mechanisms of SOCS1 and SOCS3 in macrophages are mediated via NRF-2-mediated thioredoxin upregulation resulting in the downregulation of ROS signal. Thus, our study supports the anti-oxidant role of SOCS1 and SOCS3 in the exquisite regulation of macrophage activation under oxidative stress. [BMB Reports 2020; 53(12): 640-645].

Background and purpose Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Targeting Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a promising strategy for chronic inflammatory diseases. We investigated the vasculoprotective role of suppressor of cytokine signalling-1 (SOCS1), the negative JAK/STAT regulator, in experimental AAA. Experimental approach A synthetic, cell permeable peptide (S1) mimic of SOCS1 kinase inhibitory domain to suppress STAT activation was evaluated in the well-established mouse model of elastase-induced AAA by monitoring changes in aortic diameter, cellular composition, and gene expression in abdominal aorta. S1 function was further evaluated in cultured vascular smooth muscle cells (VSMC) and macrophages exposed to elastase or elastin-derived peptides. Key results S1 peptide prevented AAA development, evidenced by reduced incidence of AAA, aortic dilation and elastin degradation, partial restoration of medial VSMC, and decreased inflammatory cells and oxidative stress in AAA tissue. Mechanistically, S1 suppressed STAT1/3 activation in aorta, downregulated cytokines and metalloproteinases, and altered the expression of cell differentiation markers by favouring anti-inflammatory M2 macrophage and contractile VSMC phenotypes. In vitro, S1 suppressed the expression of inflammatory and oxidative genes, reduced cell migration, and reversed the phenotypic switch of macrophages and VSMC. By contrast, SOCS1 silencing promoted inflammatory response. Conclusion and implications This preclinical study demonstrates the therapeutic potential of SOCS1-derived peptide to halt AAA progression by suppressing JAK/STAT-mediated inflammation and aortic dilation. S1 peptide may therefore be a valuable option for the treatment of AAA.

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient's peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype.

The epigenetic features contribute to variations in host susceptibility to SARS-CoV-2 infection and severity of symptoms. This study aimed to evaluate the relationship between the relative expression of microRNAs (miRNAs) and the severity of the disease in COVID-19 patients. The miRNA profiles were monitored during the different stages of the disease course using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression levels of the selected 11 miRNAs were measured in the blood samples collected from 73 patients (moderate

Background RING finger protein 7 (RNF7) is a highly conserved protein that functions as an E3 ubiquitin ligase. RNF7 overexpression is indicated in multiple human cancers, but its role in renal cell carcinoma (RCC) and the mechanisms underlying how it regulates the initiation and progression of RCC have not been explored. Methods Bioinformatics analysis, quantitative reverse-transcription polymerase chain reaction (RT-PCR), and Western blot were conducted to determine the expression of RNF7 in RCC tissues and cell lines. Knockdown and overexpression experiments were performed to examine the effects of RNF7 on cell viability, apoptosis, and glycolysis in vitro and on tumor growth in nude mice in vivo. Results The elevated RNF7 expression in tumor tissues of patients with RCC was correlated with poor survival. RNF7 overexpression inhibited apoptosis and promoted glycolysis in vitro and increased tumor growth in vivo by activating the JAK/STAT3 signaling pathway by ubiquitination of SOCS1. Moreover, RNF7 overexpression affected the sensitivity of RCC cells to sunitinib. Finally, STAT3 activation was necessary for transcriptional induction of RNF7. Conclusion These results demonstrate that RNF7 inhibited apoptosis, promoted glycolysis, and inhibited sunitinib sensitivity in RCC cells via ubiquitination of SOCS1, thus activating STAT3 signaling. These suggest the potential for targeting the RNF7-SOCS1/JAK/STAT3 pathway for RCC treatment.

Head and neck squamous cell carcinoma (HNSCC) is a fatal and debilitating disease, which is characterized by steady, poor survival rates despite advances in treatment. Suppressor of cytokine signaling (SOCS) 1 is up-regulated following cytokine-induced Janus kinase - signal transducer and activator of transcription (JAK-STAT) pathway activation, and inhibitors of cytokine signaling play roles in regulating cell growth and differentiation. We investigated the therapeutic potential of SOCS1 for HNSCC.We used cell lines of oropharyngeal and tongue cancers (Detroit-562 and SCC-9, respectively) and a recombinant adenovirus vector expressing SOCS1 (AdSOCS1).AdSOCS1-induced SOCS1 overexpression significantly decreased cell proliferation through GOverexpression of SOCS1 has a potent antitumor effect on HNSCC, suggesting the potential for clinical use. The varying effectiveness among cancer cells by over expression of SOCS1 may contribute to efficacy of SOCS 1 gene therapy for clinical use.

M1-polarized macrophages can improve the body's immune function. This study aimed to explore the mechanism of

Deficient mismatch repair (MMR) proteins may lead to DNA damage and microsatellite instability. Primary sclerosing cholangitis (PSC) is a risk factor for colitis-associated colon cancer. MiR-155 is suggested to act as a key regulating node, linking inflammation and tumorigenesis. However, its involvement in the chronic colitis of PSC-UC patients has not been examined. We investigated the involvement of miR-155 in the dysregulation of MMR genes and colitis in PSC patients. Colon tissue biopsies were obtained from patients with PSC, PSC with concomitant ulcerative colitis (PSC-UC), uncomplicated UC, and healthy controls (n = 10 per group). In the ascending colon of PSC and PSC-UC patients, upregulated miR-155 promoted high microsatellite instability and induced signal transducer and activator of transcription 3 (STAT-3) expression via the inhibition of suppressors of cytokine signalling 1 (SOCS1). In contrast, the absence of miR-155 overexpression in the sigmoid colon of PSC-UC patients activated the Il-6/S1PR1 signalling pathway and imbalanced the IL17/FOXP3 ratio, which reinforces chronic colitis. Functional studies on human intestinal epithelial cells (HT-29 and NCM460D) confirmed the role of miR-155 over-expression in the inhibition of MMR genes and the modulation of p53. Moreover, those cells produced more TNFα upon a lipopolysaccharide challenge, which led to the suppression of miR-155. Additionally, exposure to bile acids induced upregulation of miR-155 in Caco-2 cell lines. Thus, under different conditions, miR-155 is involved in either neoplastic transformation in the ascending colon or chronic colitis in the sigmoid colon of patients with PSC. New insight into local modulation of microRNAs, that may alter the course of the disease, could be used for further research on potential therapeutic applications.

Smoke-induced acute lung injury (ALI) is a grievous disease with high mortality. Despite advances in medical intervention, no drug has yet been approved by the Food and Drug Administration (FDA) for ALI. In this study, we reported that pretreatment with high-molecular-weight hyaluronan (1600 kDa, HA1600) alleviated pulmonary inflammation and injury in mice exposed to smoke and also upregulated long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (

Macrophages exhibit diverse functions within various tissues during the inflammatory response, and the physical properties of tissues also modulate the characteristics of macrophages. However, the underlying N6-methyladenosine (m

BackgroundIn this study, we established a chronic obstructive pulmonary disease (COPD) model by stimulating mice with cigarette smoke, and observed the effects of dendritic cells (DCs) overexpressing SOCS1 on Th17, Treg and other related cytokines in peripheral blood, bronchoalveolar lavage fluid and lung tissues of COPD mice.MethodsAfter successfully transfecting DCs with overexpressing SOCS1 (DC-SOCS1), the mice were injected with DC-SOCS1 (1 × 106), DC-SOCS1 (2 × 106) and immature DCs (1 × 106) via tail vein on days 1 and 7 of COPD fumigation modeling. After day 28 of modeling, the peripheral blood, BALF and lung tissue samples were extracted from the mice, and the changes of DCs, Th17 and Treg cells and related cytokines were detected by immunohistochemistry, immunofluorescence, HE staining, flow cytometry and ELISA.ResultsThe results showed that DC-SOCS1 was able to reduce the secretion of pro-inflammatory factors and increase the anti-inflammatory factors in the COPD mice, and the effect of high concentration (2 × 106DC-SOCS1) was better than low concentration (1 × 106DC-SOCS1). Moreover, the intervention effect was significant on day 1 compared with day 7. In the mice injected with DC-SOCS1, the expression of CD83, IL-4, Foxp3, and CCR6 was increased on day 1 than those on day 7, while IL-17 and IFN-γ was decreased.ConclusionsIntervention of COPD mice with high concentrations of DCs-SOCS1 reduced pro-inflammatory factor secretion and attenuated the inflammatory response in COPD.Trial registrationNot applicable.

Graft-versus-host disease (GVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Inflammatory signaling pathways promote T-cell activation and are involved in the pathogenesis of GVHD. Suppressor of cytokine signaling 1 (SOCS1) is a critical negative regulator for several inflammatory cytokines. However, its regulatory role in T-cell activation and GVHD has not been elucidated. Multiomics analysis of the transcriptome and chromatin structure of granulocyte-colony-stimulating-factor (G-CSF)-administered hyporesponsive T cells from healthy donors reveal that G-CSF upregulates SOCS1 by reorganizing the chromatin structure around the SOCS1 locus. Parallel in vitro and in vivo analyses demonstrate that SOCS1 is critical for restraining T cell activation. Loss of Socs1 in T cells exacerbates GVHD pathogenesis and diminishes the protective role of G-CSF in GVHD mouse models. Further analysis shows that SOCS1 inhibits T cell activation not only by inhibiting the colony-stimulating-factor 3 receptor (CSF3R)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, but also by restraining activation of the inflammasome signaling pathway. Moreover, high expression of SOCS1 in T cells from patients correlates with low acute GVHD occurrence after HSCT. Overall, these findings identify that SOCS1 is critical for inhibiting T cell activation and represents a potential target for the attenuation of GVHD.

© 2022 Nigerian Journal of Clinical Practice | Published by Wolters Kluwer . Medknow.Aims and Background: Suppressor of cytokine signaling 1 (SOCS1) is a prototype molecule of the SOCS family. Alterations in the SOCS1 expression have been reported in human cancers and some studies suggest that SOCS1 might act as a tumor suppressor in carcinogenesis. In the present study, we aimed to evaluate the association of SOCS1 promoter-1478CA/del gene polymorphism detected in DNA isolated from the tissues of patients with colorectal cancer (CRC) for histopathological characteristics and survival. Patients and Methods: For the study, we retrospectively enrolled 53 patients with resected colon due to CRC and 23 control subjects with no systemic illness. SOCS1-1478CA/del gene polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism methodology. These results were evaluated in relation to histopathological features and survival results and analyzed statistically. A P value equal to or less than 0.05 was considered significant. Results: Neither control subjects nor the CRC group showed a significant association with SOCS1-1478CA/del gene polymorphism (p = 0.248). SOCS1-1478CA/del gene polymorphism was not significantly associated with histopathological features either. However, in the overall survival (OS) analysis, those patients with the del/del allele were found to have a 3.9-fold greater risk of mortality compared to those with CA/CA allele (p = 0.05). Progression-free survival (PFS) was also significantly different in such patients (p = 0.05). Conclusion: The present study examining the association of SOCS1-1478CA/del gene polymorphism with CRC showed that CRC patients with del/del allele had both significantly shorter PFS and OS versus those with CA/CA or CA/del allele.

Importance Surgery remains the gold standard in cholesteatoma treatment. However, the rate of recurrence is significant and the development of new nonsurgical treatment alternatives is warranted. One of the possible molecular pathways to target is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Objective To investigate the JAK/STAT pathway in the middle ear mucosa in patients with acquired cholesteatoma compared with middle ear mucosa from healthy controls. Design Case-control study. Setting Linkoping University Hospital, Sweden, and Karolinska Institutet, Stockholm, Sweden. Sampling period: February 2011 to December 2016. Participants Middle ear mucosa from 26 patients with acquired cholesteatoma undergoing tympanoplasty and mastoidectomy, and 27 healthy controls undergoing translabyrinthine surgery for vestibular schwannoma or cochlear implantation was investigated. Main outcomes/measures The expression of Interleukin-7 receptor alpha, JAK1, JAK2, JAK3, STAT5A, STAT5B, and suppressor of cytokine signaling-1 (SOCS1) were quantified using quantitative polymerase chain reaction. In addition, expression level of cyclin D2, transforming growth factor beta 1, thymic stromal lymphopoietin, CD3, and CD19 was evaluated. Results In cholesteatoma-adjacent mucosa, SOCS1 was significantly upregulated (p= 0.0003) compared with healthy controls, whereas STAT5B was significantly downregulated (p = 0.0006). The expression of JAK1, JAK2, JAK3, and STAT5A did not differ significantly between groups. Conclusions and relevance To the best of our knowledge, this is the first article reporting dysregulation of the JAK/STAT pathway in cholesteatoma-adjacent mucosa. The main finding is that important players of the aforementioned pathway are significantly altered, namely SOCS1 is upregulated and STAT5B is downregulated compared with healthy controls.

Short chain fatty acids (SCFAs), the microbial metabolites of fermentable dietary fibers exert multiple beneficial effects on mammals including humans. We examined the effects of fermentable dietary fibers on suppressor of cytokine signaling 1 (SOCS1), a negative regulator of inflammatory signaling, on the intestinal epithelial cells of the mouse colon and human intestinal Caco-2 cells, specifically focusing on the role of SCFAs. Feeding fermentable fibers, guar gum (GG) and partially hydrolyzed GG (PHGG) increased SOCS1 expression in the colon and the cecal pool of some SCFAs including acetate, propionate, and butyrate. The antibiotic administration abolished the GG-mediated SOCS1 expression in the colon. In Caco-2 cells, butyrate, but not other SCFAs, increased SOCS1 expression. Taken together, fermentable fibers such as GG and PHGG upregulate the colonic SOCS1 expression, possibly through the increased production of butyrate in mice and can be a potential tool in the fight against inflammatory diseases.Abbreviations: GG: Guar gum; GPR: G protein-coupled receptor; IL: Interleukin; JAK: Janus kinase; NF- κB: Nuclear factor-kappa B; PHGG: Partially hydrolyzed guar gum; SCFA: Short chain fatty acid; SOCS: Suppressor of cytokine signaling; STAT: Signal transducer and activator of transcription; TLR: Toll-like receptor.

Dendritic cells (DCs) can orchestrate either immunogenic or tolerogenic responses to relay information on the functional state. Emerging studies indicate that circular RNAs (circRNAs) are involved in immunity; however, it remains unclear whether they govern DC development and function at the transcriptional level. In this study, we identified a central role for a novel circRNA, circSnx5, in modulating DC-driven immunity and tolerance. Ectopic circSnx5 suppresses DC activation and promotes the development of tolerogenic functions of DCs, while circSnx5 knockdown promotes their activation and inflammatory phenotype. Mechanistically, circSnx5 can act as a miR-544 sponge to attenuate miRNA-mediated target depression on suppressor of cytokine signaling 1 (SOCS1) and inhibit nuclear translocation of PU.1, regulating DC activation and function. Furthermore, the main splicing factors (SFs) were identified in DCs, of which heterogeneous nuclear ribonucleoprotein (hnRNP) C was essential for circSnx5 generation. Moreover, our data demonstrated that vaccination with circSnx5-conditioned DCs prolonged cardiac allograft survival in mice and alleviated experimental autoimmune myocarditis. Taken together, our results revealed circSnx5 as a key modulator to fine-tune DC function, suggesting that circSnx5 may serve as a potential therapeutic avenue for immune-related diseases.

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells., SOCS1 is a potent suppressor of JAK-STAT signalling responses to IFNγ and γ-chain cytokines and thereby limits inflammation. Here the authors identify and characterize heterozygous SOCS1 mutations in 10 patients from 5 unrelated families with autoimmune diseases.

Background Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer’s disease models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects. Methods Mice were treated with alogliptin (20 mg/kg/d; p.o.) for 14 days, starting 1 day prior to intracerebroventricular LPS injection (8 μg/μL in 3 μL). Results Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 and myeloid differentiation primary response 88 protein expression, nuclear factor-κB p65 content, and microRNA-155 gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein expression in the brain. Conclusion The present study sheds light on the potential neuroprotective effects of alogliptin against intracerebroventricular LPS-induced neuroinflammation and its associated memory impairment via inhibition of toll-like receptor 4/ myeloid differentiation primary response 88/ nuclear factor-κB signaling, modulation of microRNA-155/suppressor of cytokine signaling-1 expression, and enhancement of cAMP/phosphorylated cAMP response element binding protein signaling.