Self-adaptive pyroptosis-responsive nanoliposomes block pyroptosis in autoimmune inflammatory diseases

Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport.For their clinical application,nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects.Therefore,responsive drug-release strategies for inflammation treatment have been explored;however,no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation.Herein,we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes(R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate,RC-NL@DMF)that pre-cisely release encapsulated anti-pyroptotic drugs into pyroptotic cells.The activated key pyroptotic protein,the N-terminal domain of gasdermin E,selectively integrates with the cardiolipin of liposomes,thus forming pores for controlled drug release,pyroptosis,and inflammation inhibition.Therefore,RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice.Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery,suppressing pyroptosis and treating autoimmune inflammatory diseases.

Machine-learning-based models assist the prediction of pulmonary embolism in autoimmune diseases:A retrospective,multicenter study

Background:Pulmonary embolism(PE)is a severe and acute cardiovascular syndrome with high mortality among patients with autoimmune inflammatory rheumatic diseases(AIIRDs).Accurate prediction and timely intervention play a pivotal role in enhancing survival rates.However,there is a notable scarcity of practical early prediction and risk assessment systems of PE in patients with AIIRD.Methods:In the training cohort,60 AIIRD with PE cases and 180 age-,gender-,and disease-matched AIIRD non-PE cases were identified from 7254 AIIRD cases in Tongji Hospital from 2014 to 2022.Univariable logistic regression(LR)and least absolute shrinkage and selection operator(LASSO)were used to select the clinical features for further training with machine learning(ML)methods,including random forest(RF),support vector machines(SVM),neural network(NN),logistic regression(LR),gradient boosted decision tree(GBDT),classification and regression trees(CART),and C5.0 models.The performances of these models were subsequently validated using a multicenter validation cohort.Results:In the training cohort,24 and 13 clinical features were selected by univariable LR and LASSO strategies,respectively.The five ML models(RF,SVM,NN,LR,and GBDT)showed promising performances,with an area under the receiver operating characteristic(ROC)curve(AUC)of 0.962-1.000 in the training cohort and 0.969-0.999 in the validation cohort.CART and C5.0 models achieved AUCs of 0.850 and 0.932,respectively,in the training cohort.Using D-dimer as a pre-screening index,the refined C5.0 model achieved an AUC exceeding 0.948 in the training cohort and an AUC above 0.925 in the validation cohort.These results markedly outperformed the use of D-dimer levels alone.Conclusion:ML-based models are proven to be precise for predicting the onset of PE in patients with AIIRD exhibiting clinical suspicion of PE.Trial Registration:Chictr.org.cn:ChiCTR2200059599.

Long-term follow-up of children and adolescents with primary sclerosing cholangitis and autoimmune sclerosing cholangitis

BACKGROUND： Sclerosing cholangitis（SC） is a chronic cholestatic hepatobiliary disease with uncertain long-term prognosis in pediatric patients. This study aimed to evaluate longterm results in children with SC according to the types of SC.METHODS： We retrospectively followed up 25 children with SC over a period of 4-17 years（median 12）. The diagnosis of SC was based on biochemical, histological and cholangiographic findings. Patients fulfilling diagnostic criteria for probable or definite autoimmune hepatitis at the time of diagnosis were defined as having autoimmune sclerosing cholangitis（ASC）; other patients were included in a group of primary sclerosing cholangitis（PSC）. The incidence of the following complications was studied： obstructive cholangitis, portal hypertension, advanced liver disease and death associated with the primary disease.RESULTS： Fourteen（56%） patients had PSC and 11（44%） had ASC. Patients with ASC were significantly younger at the time of diagnosis（12.3 vs 15.4 years, P=0.032） and had higher Ig G levels（22.7 vs 17.2 g/L, P=0.003）. The mentioned complications occurred in 4（16%） patients with SC, exclusively in the PSC group： one patient died from colorectal cancer, one patient underwent liver transplantation and two patients, in whom severe bile duct stenosis was present at diagnosis, were endoscopically treated for acute cholangitis. Furthermore, twoother children with ASC and 2 children with PSC had elevated aminotransferase levels. The 10-year overall survival was 95.8% in all patients, 100% in patients without complicated liver disease, and 75.0% in patients with complications.CONCLUSION： In children, ASC is a frequent type of SC, whose prognosis may be better than that in patients with PSC.

Total glucosides of paeony alleviates Sjogren syndrome through inhibiting inflammatory responses in mice

OBJECTIVE To study the therapeutic effects of TGP on SS both in C57BL/6J mice immunized by immu⁃nological induction(SS mice)and NOD/ShiltJNju(NOD)mice.METHODS TGP(180,360,720 mg·kg^-1)was intragastri⁃cally administered for 6 or 16 weeks for SS mice and NOD mice,respectively.Weekly food and water intake,saliva flow,submandibular gland(SMG)and spleen index,and SMG pathology were measured.ELISA was used to evaluate serum interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ)and autoantigens(SSA/Ro,SSB/La,andα-fodrin).Real-time PCR and Luminex liquid suspension chip assay were applied to analyze SMG inflammatory cytokines mRNA TNF-α,IL-17A,CXCL9,CXCL13,and B-cell activating factor(BAFF)and protein(IL-1β,IL-6,TNF-α,and IFN-γ)expres⁃sion.RESULTS Compared with SS mice,TGP(720 mg·kg^-1)treatment increased saliva flow,reduced organ indexes,and decreased serum IL-6 and IFN-γ concentration.TGP(360 mg·kg^-1)treatment decreased serum IFN-γ concentra⁃tion.TGP(180,360,720 mg·kg^-1)treatment improved SMG pathological damage.Compared with NOD mice,the saliva flowincreased from 9 to 15 weeks of administration.After 2 weeks of administration,TGP(720 mg·kg^-1)treatment decreased serum SSA/Ro,SSB/La and a-fodrin concentration,increased SMG index,inhibited SMG IFN-γ concentra⁃tion,and down-regulated SMG TNF-α,IL-17A,CXCL9,CXCL13 and BAFF mRNA expression.TGP(360 mg·kg^-1)treat⁃ment decreased serum SSB/La and a-fodrin,and SMG TNF-α and IFN-γ concentration,and down-regulated SMG TNF-α,IL-17A,CXCL9 and BAFF mRNA expression.TGP(180 mg·kg^-1)treatment decreased serum SSB/La,a-fodrin,and SMG IL-1β concentration,and down-regulated SMG TNF-α,IL-17A and BAFF mRNA expression.After 8 weeks of administration,TGP(180,360,720 mg·kg^-1)treatment increased SMG index,and decreased serum a-fodrin concentra⁃tion.TGP(720 mg·kg^-1)treatment down-regulated mRNA expression of SMG TNF-α,IL-17A,CXCL9,CXCL13,and BAFF.TGP(360 mg·kg^-1)treatment reduced mRNA expression of TNF-α,CXCL9,CXCL13 and BAFF,and concentra⁃tion of IL-6 and TNF-α.TGP(180 mg·kg^-1)treatment down-regulated mRNA expression of TNF-α,CXCL9,and CXCL13,and decreased IL-6 and TNF-αconcentration in SMG.After 16 weeks of administration,TGP(180,360,720 mg·kg^-1)treatment reduced serum SSA/Ro and a-fodrin concentration,increased SMG index,and decreased SMG CXCL13 and BAFF mRNA expression.TGP(360,720 mg·kg^-1)treatment decreased serum SSB/Laconcentration and SMG TNF-α,IL-17A and CXCL9 mRNA expression.Besides,TGP(180,360,720 mg·kg^-1)treatment alleviated the pathological damage of SMG after 2 and 16 weeks of administration.CONCLUSION TGP has a certain therapeutic effect onmice through inhibiting inflammatory responses.

Induced Foxp3^(+)regulatory T cells:a potential new weapon to treat autoimmune and inflammatory diseases?

Foxp3^(+)T regulatory cells(Tregs)consisting of natural and induced Treg subsets play a crucial role in the maintenance of immune homeostasis against self-antigen.The actions designed to correct defects in numbers or functions of Tregs may be therapeutic in the treatment of autoimmune diseases.While recent studies demonstrated that natural Tregs are instable and dysfunctional in the in-flammatory condition,induced Tregs(iTregs)may have a different feature.Here we review the progress of iTregs,particularly focus on their stability and function in the established autoimmune diseases.The advantage of iTregs as therapeutics used under inflammatory conditions is highlighted.Proper generation and manipulation of iTregs used for cellular therapy may provide a promise for the treatment of many autoimmune and inflammatory diseases.