Role of dendritic cells in MYD88-mediated immune recognition and osteoinduction initiated by the implantation of biomaterials

Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects.Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials.Previous studies have mainly focused on innate immune cells such as macrophages.In our previous work,we found that T lymphocytes,as adaptive immune cells,are also essential in the osteoinduction procedure.As the most important antigen-presenting cell,whether dendritic cells(DCs)can recognize non-antigen biomaterials and participate in osteoinduction was still unclear.In this study,we found that surgical trauma associated with materials implantation induces necrocytosis,and this causes the release of high mobility group protein-1(HMGB1),which is adsorbed on the surface of bone substitute materials.Subsequently,HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells,and the inflammatory response was activated.Finally,activated DCs release regeneration-related chemokines,recruit mesenchymal stem cells,and initiate the osteoinduction process.This study sheds light on the immune-regeneration process after bone substitute materials implantation,points out a potential direction for the development of bone substitute materials,and provides guidance for the development of clinical surgical methods.

Tim4 deficiency reduces CD301b+macrophage and aggravates periodontitis bone loss

Periodontitis is a common chronic inflammatory disease that causes the periodontal bone destruction and may ultimately result in tooth loss.With the progression of periodontitis,the osteoimmunology microenvironment in periodontitis is damaged and leads to the formation of pathological alveolar bone resorption.CD301b^(+)macrophages are specific to the osteoimmunology microenvironment,and are emerging as vital booster for conducting bone regeneration.However,the key upstream targets of CD301b^(+)macrophages and their potential mechanism in periodontitis remain elusive.In this study,we concentrated on the role of Tim4,a latent upstream regulator of CD301b^(+)macrophages.We first demonstrated that the transcription level of Timd4(gene name of Tim4)in CD301b^(+)macrophages was significantly upregulated compared to CD301b^(-) macrophages via high-throughput RNA sequencing.Moreover,several Tim4-related functions such as apoptotic cell clearance,phagocytosis and engulfment were positively regulated by CD301b^(+)macrophages.The single-cell RNA sequencing analysis subsequently discovered that Cd301b and Timd4 were specifically co-expressed in macrophages.The following flow cytometric analysis indicated that Tim4 positive expression rates in total macrophages shared highly synchronized dynamic changes with the proportions of CD301b^(+)macrophages as periodontitis progressed.Furthermore,the deficiency of Tim4 in mice decreased CD301b^(+)macrophages and eventually magnified alveolar bone resorption in periodontitis.Additionally,Tim4 controlled the p38 MAPK signaling pathway to ultimately mediate CD301b^(+)macrophages phenotype.In a word,Tim4 might regulate CD301b^(+)macrophages through p38 MAPK signaling pathway in periodontitis,which provided new insights into periodontitis immunoregulation as well as help to develop innovative therapeutic targets and treatment strategies for periodontitis.

Antibiotic resistance and cagA gene correlation:A looming crisis of Helicobacter pylori

AIM:To determine antibiotic resistance of Helicobacter pylori(H.pylori) in Pakistan and its correlation with host and pathogen associated factors.METHODS:A total of 178 strains of H.pylori were isolated from gastric biopsies of dyspeptic patients.Susceptibility patterns against first and second-line antibiotics were determined and trends of resistance were analyzed in relation to the sampling period,gastric conditions and cagA gene carriage.The effect of cagA gene on the acquisition of resistance was investigated by mutant selection assay.RESULTS:The observations showed that monoresistant strains were prevalent with rates of 89% for metronidazole,36% for clarithromycin,37% for amoxicillin,18.5% for ofloxacin and 12% for tetracycline.Furthermore,clarithromycin resistance was on the rise from 2005 to 2008(32% vs 38%,P = 0.004) and it is significantly observed in non ulcerative dyspeptic patients compared to gastritis,gastric ulcer and duodenal ulcer cases(53% vs 20%,18% and 19%,P = 0.000).On the contrary,metronidazole and ofloxacin resistance were more common in gastritis and gastric ulcer cases.Distribution analysis and frequencies of resistant mutants in vitro correlated with the absence of cagA gene with metronidazole and ofloxacin resistance.CONCLUSION:The study confirms the alarming levels of antibiotic resistance associated with the degree of gastric inflammation and cagA gene carriage in H.pylori strains.

Preliminary exploration of the mechanism of compound Qinlan oral liquid against new coronavirus pneumonia based on network pharmacology and molecular docking technology

Objective:Applying Traditional Chinese Medicine(TCM)network pharmacology and molecular docking technology to explore the mechanism of anti-coronary virus pneumonia(Corona Virus Disease 2019,COVID-19)of Compound Qinlan oral liquid.Methods:Traditional Chinese Medicines Integrated Database(TCMID),Traditional Chinese Medicine Systems Pharmacology(TCMSP),OMIM,GeneCards,String and others online databases were used for building a series of networks,and selecting the core targets and analyzing the signal pathways.Finally,Discovery Studio 2016 software was used to conduct molecular docking of the main compounds(Chinese Medicine Legal Quality Control Compound)of Compound Qinlan oral liquid with key targets ACE2,3CLpro,etc.Results:the results showed that Compound Qinlan oral liquid has specific effects in lung,heart and stomach diseases.The Compound Qinlan oral liquid compound-pneumonia target network contained 98 compounds and 184 corresponding targets,and the core targets involved INS,TP53,IL6,VEGFA,ALB and JUN.GO(GeneOntology)function enrichment analysis yielded 653 GO entries,and KEGG(KyotoEncyclopedia of Genes and Genomes)enrichment screening yielded 112 related pathways,including hypoxia inducible factor-1(HIF-1)and Toll-like receptor(TLRs)signaling pathway related to pneumonia,as well as Influenza A signaling pathway and Hepatitis B signaling pathway related to microbial infection.The results of molecular docking show that Isochlorogenic acid C,Baicalein,etc have good binding capacity with ACE2,3CLpro,AKT1 and other proteins.Conclusion:In this paper,we preliminarily explored the potential therapeutic mechanism for Compound Qinlan oral liquid to against coronavirus pneumonia(COVID-19)and predicted the active ingredients.We hope that the results will help to further study on the active ingredients and mechanism of Compound Qinlan oral liquid for anti-COVID-19.

Targeting a disintegrin and metalloprotease(ADAM)17-CD122 axis enhances CD8^(+)T cell effector differentiation and anti-tumor immunity

CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins.Here,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T cells.Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors.Mechanistically,ADAM17 regulated CD8^(+)T cells through cleavage of membrane CD122.ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T cells.Intriguingly,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid tumors.Our findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.

Hepatitis B virus,HBx mutants and their role in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is one of the leading causes of death induced by cancer in the modern world and majority of the cases are related to chronic hepatitis B virus(HBV)infection.HBV-encoded X protein(HBx)is known to play a pivotal role in the pathogenesis of viral induced HCC.HBx is a multifunctional protein of17 kDa which modulates several cellular processes by direct or indirect interaction with a repertoire of host factors resulting in HCC.HBX might interfere with several cellular processes such as oxidative stress,DNA repair,signal transduction,transcription,protein degradation,cell cycle progression and apoptosis.A number of reports have indicated that HBx is one of the most common viral ORFs that is often integrated into the host genome and its sequence variants play a crucial role in HCC.By mutational or deletion analysis it was shown that carboxy terminal of HBx has a likely role in protein-protein interactions,transcriptional transactivation,DNA repair,cell,signaling and pathogenesis of HCC.The accumulated evidence thus far suggests that it is difficult to understand the mechanistic nature of HBx associated HCC,and HBx mediated transcriptional transactivation and signaling pathways may be a major determinant.This article addresses the role of HBx in the development of HCC with particular emphasis on HBx mutants and their putative targets.

Potential mechanisms of hepatitis B virus induced liver injury

Chronic active hepatitis(CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma.The histological end points of CAH are chronic inflammation,fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers.The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis,inflammation and cytokine production and liver scaring(fibrosis).The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components.The viral and cellular factors that contribute to liver injury are discussed in this article.Liver injury caused by the viral infection affects many cellular processes such as cell signaling,apoptosis,transcription,DNA repair which in turn induce radical effects on cell survival,growth,transformation and maintenance.The consequence of such perturbations is resulted in the alteration of bile secretion,gluconeogenesis,glycolysis,detoxification and metabolism of carbohydrates,proteins,fat and balance of nutrients.The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury.

Hepatitis C virus and neurological damage

Chronic hepatitis C virus(HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.

A One-Health Sampling Strategy to Explore the Dissemination and Relationship Between Colistin Resistance in Human,Animal,and Environmental Sectors in Laos

This study was designed to investigate the molecular epidemiology of mobile colistin resistance(mcr)using a"One-Health"approach in Laos and to predict whether any dominant plasmid backbone and/or strain type influences the dissemination of mcr.We collected 673 samples from humans(rectal normal flora),poultry,and the environment(water,flies,birds,etc.)in Vientiane,Lao People’s Democratic Republic(Laos),from May to September 2018.A total of 238 Escherichia coli(E.coli)isolated from nonduplicative samples,consisting of 98 MCR-positive E.coli(MCRPEC)("mcr"denotes the gene encoding mobile colistin resistance,and"MCR"denotes the subsequent protein encoded by mcr)and 140 MCRnegative E.coli(MCRNEC),were characterized by phenotype and Illumina sequencing.A subset of MCRPEC was selected for Min ION sequencing,conjugation assay,plasmid stability,and growth kinetics in vitro.The prevalence of MCRPEC was found to be 14.6%(98/673),with the highest prevalence in human rectal swabs(45.9%(45/98),p<0.0001,odds ratio(OR):0.125,95% confidence interval(CI):0.077-0.202).The percentages of MCRPEC from other samples were 14.3%(2/14)in dog feces,12.0%(24/200)in flies,11.0%(11/100)in chicken meat,8.9%(8/90)in chicken cloacal,8.0%(4/50)in chicken caeca,and 7.5%(4/53)in wastewater.MCRPEC was significantly more resistant to co-amoxiclav,sulfamethoxazoletrimethoprim,levofloxacin,ciprofloxacin,and gentamicin than MCRNEC(p<0.05).Genomic analysis revealed the distribution of MCRPEC among diverse clonal types.The putative plasmid Inc types associated with mcr-1 were Inc X4,Inc HI2,Inc P1,Inc I2,and Inc FIA,and those associated with mcr-3 were Inc FII,Inc FIA,Inc FIB,Inc P1,and Inc R.Recovery of highly similar plasmids from both flies and other sampling sectors implied the role of flies in the dissemination of mcr-1.mcr-positive plasmids were shown to be conjugative,and a significantly high transfer rate into a hypervirulent clone ST1193 was observed.Plasmids containing mcr irrespective of Inc type were highly stable and invariably did not exert a fitness effect upon introduction into a new host.These findings signify the urgent need for a standard infection control program to radically decontaminate the source of resistance.

Ubiquitin-specific protease 24 promotes EV71 infection by restricting K63-linked polyubiquitination of TBK1

TANK-binding kinase 1(TBK1)is an essential protein kinase for activation of interferon regulatory factor 3(IRF3)and induction of the type I interferons(IFN-I).Although the biochemical regulation of TBK1 activation has been studied,little is known about how enterovirus 71(EV71)employs the deubiquitinases(DUBs)to regulate TBK1 activation for viral immune evasion.Here,we found that EV71 infection upregulated the expression of ubiquitinspecific protease 24(USP24).Further studies revealed that USP24 physically interacted with TBK1,and can reduce K63-linked polyubiquitination of TBK1.Knockdown of USP24 upregulated TBK1 K63-linked polyubiquitination,promoted the phosphorylation and nuclear translocation of IRF3,and in turn improved IFN-I production during EV71 infection.As a consequence,USP24 knockdown dramatically inhibited EV71 infection.This study revealed USP24 as a novel regulator of TBK1 activation,which promotes the understanding of immune evasion mechanisms of EV71 and could provide a potential strategy for treatment of EV71 infection.

CD301b^(+) macrophage: the new booster for activating bone regeneration in periodontitis treatment

Periodontal bone regeneration is a major challenge in the treatment of periodontitis.Currently the main obstacle is the difficulty of restoring the regenerative vitality of periodontal osteoblast lineages suppressed by inflammation,via conventional treatment.CD301b^(+)macrophages were recently identified as a subpopulation that is characteristic of a regenerative environment,but their role in periodontal bone repair has not been reported.

Etiology of invasive candidosis agents in Russia： a multicenter epidemiological survey

A multicenter prospective epidemiological survey on the etiologic agents of invasive candidosis was conducted in Russia in the period of 2012-2014. Samples were collected from 284 patients with invasive candidosis and Candida species isolated by culture. The species were identified by DNA sequencing and MALDI-TOF mass- spectrometry. A total of 322 isolates were recovered, in which 96% of Candida species belonged to six major species, namely, C. albicans （43.2%）, C. parapsilosis （20.2%）, C. glabrata （11.5%）, C. tropicalis （9.6%）, C. krusei （6.2%）, and C. guilliermondii （5.3%）. Most Candida species were isolated from blood samples （83.23%）. Notably, the prevalence rate of C. albicans reduced from 52.38% to 32.79% （2012 vs. 2014） （P = 0.01） whereas that of non-C. albicans increased from 47.62% （2012） to 67.21% （2014） （P〈 0.01）. Species distribution differed among geographical regions; specifically, the prevalence rate of C. albicans as an etiologic agent of invasive candidosis in Siberian Federal region was significantly higher than that in other Federal regions. Results indicated a shift from C. albicans to non-C, albicans. Therefore, a detailed investigation on the contributing factors and appropriate treatment of invasive candidosis is needed.

T cells in health and disease

T cells are crucial for immune functions to maintain health and prevent disease.T cell development occurs in a stepwise process in the thymus and mainly generates CD4^(+)and CD8^(+)T cell subsets.Upon antigen stimulation,naïve T cells differentiate into CD4^(+)helper and CD8^(+)cytotoxic effector and memory cells,mediating direct killing.

SEL1L preserves CD8^(+) T-cell survival and homeostasis by fine-tuning PERK signaling and the IL-15 receptor-mediated mTORC1 axis

SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis.Herein,we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells,which was further validated by adoptive transfer experiments or bone marrow chimera experiments,accompanied by the induction of multiple forms of cell death.Furthermore,SEL1L deficiency selectively disrupted naïve CD8+T-cell homeostasis,as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset.We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift,which was largely attributable to enhanced expression of the IL-15 receptorαandβchains.Mechanistically,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l−/−CD8+T cells harbored excessive ER stress,particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway,which was alleviated by supplementing IL-7 or IL-15.Importantly,PERK inhibition greatly resolved the survival defects of Sel1l−/−CD8+T cells.In addition,IRE1αdeficiency decreased mTORC1 signaling in Sel1l−/−naïve CD8+T cells by downregulating the IL-15 receptorαchain.Altogether,these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.

Identification of arylamine N-acetyltransferase inhibitors as an approach towards novel anti-tuberculars

New anti-tubercular drugs and drug targets are urgently needed to reduce the time for treatment and also to identify agents that will be effective against Mycobacterium tuberculosis persisting intracellularly.Mycobacteria have a unique cell wall.Deletion of the gene for arylamine N-acetyltransferase(NAT)decreases mycobacterial cell wall lipids,particularly the distinctive mycolates,and also increases antibiotic susceptibility and killing within macrophage of Mycobacterium bovis BCG.The nat gene and its associated gene cluster are almost identical in sequence in M.bovis BCG and M.tuberculosis.The gene cluster is essential for intracellular survival of mycobacteria.We have therefore used pure NAT protein for high-throughput screening to identify several classes of small molecules that inhibit NAT activity.Here,we characterize one class of such molecules—triazoles—in relation to its effects on the target enzyme and on both M.bovis BCG and M.tuberculosis.The most potent triazole mimics the effects of deletion of the nat gene on growth,lipid disruption and intracellular survival.We also present the structure-activity relationship between NAT inhibition and effects on mycobacterial growth,and use ligand-protein analysis to give further insight into the structure-activity relationships.We conclude that screening a chemical library with NAT protein yields compounds that have high potential as anti-tubercular agents and that the inhibitors will allow further exploration of the biochemical pathway in which NAT is involved.

CD301b^(+) macrophages mediate angiogenesis of calcium phosphate bioceramics by CaN/NFATc1/VEGF axis

Calcium phosphate(CaP)bioceramics are important for tissue regeneration and immune response,yet how CaP bioceramics influence these biological processes remains unclear.Recently,the role of immune cells in biomaterial-mediated regeneration,especially macrophages,has been well concerned.CD301b^(+)macrophages were a new subset of macrophages we have discovered,which were required for bioceramics-mediated bone regeneration.Nevertheless,the impact of CD301b^(+)macrophages on angiogenesis,which is a vital prerequisite to bone formation is yet indistinct.Herein,we found that CD301b^(+)macrophages were closely correlated to angiogenesis of CaP bioceramics.Additionally,depletion of CD301b^(+)macrophages led to the failure of angiogenesis.We showed that store-operated Ca^(2+)entry and calcineurin signals regulated the VEGF expression of CD301b^(+)macrophages via the NFATc1/VEGF axis.Inhibition of calcineurin effectively impaired angiogenesis via decreasing the infiltration of CD301b^(+)macrophages.These findings provided a potential immunomodulatory strategy to optimize the integration of angiogenesis and bone tissue engineering scaffold materials.

Chimeric Antigen Receptor-Modified Immune Cells for Eradication of HIV Reservoirs

Host immune surveillance can achieve powerful clearance of infectious pathogens.Acute human immunodeficiency virus type I(HIV-1)infection can establish viral reservoirs in humans,and persistent chronic activation by the virus exhausts the immune system and ultimately causes acquired immunodeficiency syndrome.Although antiretroviral therapy(ART)can reduce the viral load and viremia in patients,latent HIV-1 reservoirs are still the biggest challenge that needs to be overcome to eradicate the virus.However,the low or absent viral antigen expression and epitope mutation caused during durable ART result in host immune escape and reservoir cell inaccessibility.In addition,durable ART accompanied by inflammation and persistent activation of immune cells,especially dysfunction and/or exhaustion of T cells.With the development of immunology,genetics,and genetic engineering technology,researchers can construct chimeric antigen receptors(CARs)to modify immune cells to enhance HIV clearance.The important research goals of creating CARs tomodify natural killer(NK)and T cells are an attempt to enhance the functional effects of immune cells and restore the function of the immune system.This article reviews the latent characteristics of HIV,the development of CARmolecules,and the strategies for reprogramming T cells and NK cells with CARs,and aims to clear the HIV reservoirs and related potential problems.

A host E3 ubiquitin ligase regulates Salmonella virulence by targeting an SPI-2 effector involved in SIF biogenesis

Salmonella Typhimurium creates an intracellular niche for its replication by utilizing a large cohort of effectors,including several that function to interfere with host ubiquitin signaling.Although the mechanism of action of many such effectors has been elucidated,how the interplay between the host ubiquitin network and bacterial virulence factors dictates the outcome of infection largely remains undefined.In this study,we found that the SPI‐2 effector SseK3 inhibits SNARE pairing to promote the formation of a Salmonella‐induced filament by Arg‐GlcNAcylation of SNARE proteins,including SNAP25,VAMP8,and Syntaxin.Further study reveals that host cells counteract the activity of SseK3 by inducing the expression of the E3 ubiquitin ligase TRIM32,which catalyzes K48‐linked ubiquitination on SseK3 and targets its membrane‐associated portion for degradation.Hence,TRIM32 antagonizes SNAP25 Arg‐GlcNAcylation induced by SseK3 to restrict Salmonella‐induced filament biogenesis and Salmonella replication.Our study reveals a mechanism by which host cells inhibit bacterial replication by eliminating specific virulence factors.

The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling

The E3 ubiquitin ligase(E3)-mediated ubiquitination and deubiquitinase(DUB)-mediated deubiquitination processes are closely associated with the occurrence and development of colonic inflammation.Ovarian tumor deubiquitinase 1(OTUD1)is involved in immunoregulatory functions linked to infectious diseases.However,the effect of OTUD1 on intestinal immune responses during colonic inflammatory disorders such as inflammatory bowel disease(IBD)remains unclear.Here,we show that loss of OTUD1 in mice contributes to the pathogenesis of dextran sulfate sodium(DSS)-induced colitis via excessive release of proinflammatory cytokines.In addition,bone marrow transplantation experiments revealed that OTUD1 in hematopoietic cells plays a dominant role in protection against colitis.Mechanistically,OTUD1 physically interacts with receptor-interacting serine/threonine-protein kinase 1(RIPK1)and selectively cleaves K63-linked polyubiquitin chains from RIPK1 to inhibit the recruitment of NF-κB essential modulator(NEMO).Moreover,the expression of OTUD1 in mucosa samples from ulcerative colitis(UC)patients was lower than that in mucosa samples from healthy controls.Furthermore,we demonstrate that the UC-associated OTUD1 G430V mutation abolishes the ability of OTUD1 to inhibit RIPK1-mediated NF-κB activation and intestinal inflammation.Taken together,our study unveils a previously unexplored role of OTUD1 in moderating intestinal inflammation by inhibiting RIPK1-mediated NF-κB activation,suggesting that the OTUD1-RIPK1 axis could be a potential target for the treatment of IBD.