The Journal of Clinical Investigation最新文献

{"title":"Targeting the IL-36 receptor with spesolimab mitigates residual inflammation and prevents generalized pustular psoriasis flares.","authors":"James G Krueger,Mrinal K Sarkar,Mark G Lebwohl,Akimichi Morita,Kenneth Gordon,Rachael Bogle,Christopher Cole,Anthony Coon,Richard G Langley,Richard B Warren,Arash Mostaghimi,Bruce Strober,A David Burden,Min Zheng,Aaron R Mangold,Milan J Anadkat,Jonathan N Barker,Joseph F Merola,Lam C Tsoi,Ming Tang,Kolja Becker,Denis Delic,Christian Thoma,Johann E Gudjonsson","doi":"10.1172/jci188530","DOIUrl":"https://doi.org/10.1172/jci188530","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"70 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vaccines in cancer treatment and prevention: the time is now.","authors":"William Becker,W Kimryn Rathmell","doi":"10.1172/jci195673","DOIUrl":"https://doi.org/10.1172/jci195673","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune regeneration: implications for cancer immunotherapy and beyond.","authors":"Steven L Reiner","doi":"10.1172/jci192731","DOIUrl":"https://doi.org/10.1172/jci192731","url":null,"abstract":"Cancer care is being transformed by therapies leveraging T lymphocytes to attack tumor cells. In parallel, recent basic discoveries have converged into a framework of lymphocyte-dependent immunity as a regenerative process that is sometimes outstripped by high-level engagement. In a stem cell-like fashion, selected T cells must balance mutually opposing demands of differentiation and self-renewal. Activating versus inhibitory signals to T cells instruct opposing cell metabolism, linked to alternative cell fates that arise in sibling cells through lopsided information transfer. Emerging studies indicate that durable immunotherapy response may be limited by the abundance of self-renewing T cells. Leveraging of basic discoveries of regenerative signaling to bolster sustained, stem-like output of freshly differentiated T cells is offering new strategies to overcome cancer immunotherapy resistance. Lymphocyte regeneration may also sustain harmful autoimmune attack. Undercutting the self-renewal of pathogenic clones may thus emerge as a therapeutic strategy for autoimmune diseases.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thwarting amyloidosis: IL-17 as a disease modifier along the gut/brain axis.","authors":"Wade K Self,David M Holtzman","doi":"10.1172/jci194443","DOIUrl":"https://doi.org/10.1172/jci194443","url":null,"abstract":"Recent studies have highlighted a possible role for gut microbiota in modulating Alzheimer's disease pathology, particularly through the actions of gut-derived metabolites and their influence on the immune system. In this issue of the JCI, Chandra et al. reveal that circulating levels of the gut microbiota-derived metabolite propionate affected amyloid burden and glial activation in a mouse model of Aβ amyloidosis. The study also identifies a mechanism for the therapeutic benefit of propionate supplementation, showing that propionate lowered peripheral IL-17 and suppressed Th17 cell activity. These results support the idea of therapeutic targeting of the gut/brain/immune axis, particularly via modulation of Th17 responses, and suggest translational strategies involving microbiome-based or immunological interventions for dementia prevention and treatment.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cingulate retinoic acid signaling regulates neuropathic pain and comorbid anxiodepression via extracellular matrix homeostasis.","authors":"Zhen-Zhen Li,Wan-Neng Liu,Ke-Xin Liu,Zhi-Wei Dou,Rui Zhao,Yun Chen,Meng-Meng Wang,Tao-Zhi Wang,Fei Wang,Wen-Juan Han,Wen-Guang Chu,Xing-Xing Zheng,Rou-Gang Xie,Hua Yuan,Xiao-Fan Jiang,Xiao-Long Sun,Ceng Luo,Shengxi Wu","doi":"10.1172/jci190539","DOIUrl":"https://doi.org/10.1172/jci190539","url":null,"abstract":"Neuropathic pain is often comorbid with affective disorders. Synaptic plasticity in anterior cingulate cortex (ACC) is assumed to be a crucial interface for pain perception and emotion. Laminin β1 (LAMB1), a key element of extracellular matrix (ECM) in ACC was recently revealed to convey extracellular alterations to intracellular synaptic plasticity and underlie neuropathic pain and aversive emotion. However, it remains elusive what triggers activity-dependent changes of LAMB1 and ECM remodeling after nerve injury. Here, we uncovered a key role of retinoic acid (RA)/RARB signaling in neuropathic pain and associated anxiodepression via regulation of ECM homeostasis. We showed that nerve injury reduced RA level in the serum and ACC in mice and human, which brought about downregulation of its corresponding receptor, RARB. Overexpressing RARB relieved pain hypersensitivity and comorbid anxiodepression, while silencing RARB exacerbated pain sensitivity and induced anxiodepression. Further mechanistic analysis revealed that RARB maintained ECM homeostasis via transcriptional regulation of LAMB1, reversing abnormal synaptic plasticity and eventually improved neuropathic pain and aversive emotion. Taken together with our previous study, we revealed an intracellular-extracellular-intracellular feedforward regulatory network in modulating pain plasticity. Moreover, we identified cingulate RA/RARB signaling as a promising therapeutic target for treatment of neuropathic pain and associated anxiodepression.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.","authors":"Siera A Tomishima,Dale D Kim,Nadia Porter,Ipsita Guha,Asif A Dar,Yohaniz Ortega-Burgos,Jennifer Roof,Hossein Fazelinia,Lynn A Spruce,Christopher S Thom,Robert L Bowman,Paula M Oliver","doi":"10.1172/jci180913","DOIUrl":"https://doi.org/10.1172/jci180913","url":null,"abstract":"The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny is controlled by the JAK/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (Cul5), can regulate JAK/STAT signaling by degrading signaling intermediates. Here we report that mice lacking Cul5 in hematopoietic cells (Cul5Vav-Cre) have increased numbers of HSPCs, splenomegaly, and extramedullary hematopoiesis. Differentiation in Cul5Vav-Cre mice is myeloid- and megakaryocyte-biased, resulting in leukocytosis, anemia and thrombocytosis. Cul5Vav-Cre mice increased HSC proliferation and circulation, associated with a decrease in CXCR4 surface expression. In bone marrow cells, we identified LRRC41 co-immunoprecipitated with CUL5, and vice versa, supporting that CRL5 forms a complex with LRRC41. We identified an accumulation of LRRC41 and STAT5 in Cul5Vav-Cre HSCs during IL-3 stimulation, supporting their regulation by Cul5. Whole cell proteome (WCP) analysis of HSPCs from Cul5Vav-Cre bone marrow identified upregulation of many STAT5 target genes and associated pathways. Finally, JAK1/2 inhibition with ruxolitinib normalized hematopoiesis in Cul5Vav-Cre mice. These studies demonstrate the function of Cul5 in HSC function, stem cell fate decisions, and regulation of IL-3 signaling.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamics of Th1/Th17 responses and antimicrobial pathways in leprosy skin lesions.","authors":"Priscila R Andrade,Feiyang Ma,Jing Lu,Jaime de Anda,Ernest Y Lee,George W Agak,Craig J Dobry,Bruno J de Andrade Silva,Rosane Mb Teles,Lilah A Mansky,Jonathan Perrie,Dennis J Montoya,Bryan D Bryson,Johann E Gudjonsson,Gerard Cl Wong,Euzenir N Sarno,Matteo Pellegrini,Robert L Modlin","doi":"10.1172/jci190736","DOIUrl":"https://doi.org/10.1172/jci190736","url":null,"abstract":"BACKGROUNDReversal reactions (RR) in leprosy are acute immune episodes marked by inflammation and bacterial clearance, offering a model to study the dynamics of host responses to Mycobacterium leprae. These episodes are often severe and difficult to treat, frequently progressing to permanent disabilities. We aimed to characterize the immune mechanisms and identify antimicrobial effectors during RR.METHODSWe performed RNA sequencing on paired skin biopsy specimens from nine leprosy patients collected before and at RR diagnosis, followed by differential gene expression and functional analysis. A machine learning classifier was applied to predict membrane-permeabilizing proteins. Antimicrobial activity was assessed in M. leprae-infected macrophages and axenic cultures.RESULTSIn the paired pre-RR and RR biopsy specimens, a 64-gene antimicrobial response signature was upregulated during RR and correlated with reduced M. leprae burden. Predicted upstream regulators included IL-1β, TNF, IFN-γ, and IL-17, indicating activation of both Th1 and Th17 pathways. A machine learning classifier identified 28 genes with predicted membrane-permeabilizing antimicrobial activity, including S100A8. Four proteins (S100A7, S100A8, CCL17, CCL19) demonstrated antimicrobial activity against M. leprae in vitro. Scanning electron microscopy revealed membrane damage in bacteria exposed to these proteins.CONCLUSIONRR is associated with a robust antimicrobial gene program regulated by Th1/Th17 cytokines. We identified potentially novel host antimicrobial effectors that exhibit activity against M. leprae, suggesting potential strategies to bolster Th1/Th17 responses for combating intracellular mycobacterial infections.FUNDINGNIH grants R01 AI022553, R01 AR040312, R01 AR073252, R01 AI166313, R01 AI169526, P50 AR080594, 4R37 AI052453-21, and NSF grant DMR2325840.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lung adenocarcinoma-derived IFN-γ promotes growth by modulating CD8+ T cell production of CCR5 chemokines.","authors":"Christina Kratzmeier,Mojtaba Taheri,Zhongcheng Mei,Isabelle Lim,May A Khalil,Brandon Carter-Cooper,Rachel E Fanaroff,Chin S Ong,Eric B Schneider,Stephanie Chang,Erica Leyder,Dongge Li,Irina G Luzina,Anirban Banerjee,Alexander Sasha Krupnick","doi":"10.1172/jci191070","DOIUrl":"https://doi.org/10.1172/jci191070","url":null,"abstract":"Since the lung is a mucosal barrier organ with a unique immunologic environment, mechanisms of immunoregulation in lung cancer may differ from those of other malignancies. Consistent with this notion, we found that CD8+ T cells play a paradoxical role in facilitating, rather than ameliorating, the growth of multiple lung adenocarcinoma models. These include spontaneous, carcinogen-induced, and transplantable tumor cell line models. Specifically, we found that CD8+ T cells promote homing of CD4+Foxp3+ T regulatory cells to the tumor bed by increasing levels of CCR5 chemokines in the tumor microenvironment in an IFN-γ and TNF-α dependent manner. Contrary to their canonical role, these Th1 cytokines contributed to accelerated growth of murine lung adenocarcinomas while suppressing the growth of other malignancies. Surprisingly, lung cancer cells themselves can serve as a dominant source of IFN-γ, and deletion of this cytokine from cancer cells using CRISPR/Cas-9 decreases tumor growth. Importantly for translational applications, a high level of IFN-γ was also found in human lung cancer patients at both the mRNA and protein level. Our data outlines what we deem a novel and previously undefined lung cancer specific immunoregulatory pathway that may be harnessed to tailor immune based therapy specifically for this malignancy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature-positive castration-resistant prostate cancer.","authors":"Shipra Shukla,Dan Li,Woo Hyun Cho,Dana M Schoeps,Holly M Nguyen,Jennifer L Conner,Marjorie L Roskes,Anisha Tehim,Gabriella Bayshtok,Mohini R Pachai,Juan Yan,Nicholas A Teri,Eric Campeau,Sarah Attwell,Patrick Trojer,Irina Ostrovnaya,Anuradha Gopalan,Ekta Khurana,Eva Corey,Ping Chi,Yu Chen","doi":"10.1172/jci180378","DOIUrl":"https://doi.org/10.1172/jci180378","url":null,"abstract":"A subgroup (~20-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"187 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical, tumor and product features associated with outcomes after axicabtagene ciloleucel therapy in follicular lymphoma.","authors":"Soumya Poddar,Jiali Yan,Gayatri Tiwari,Darawan Rinchai,Justin Budka,Wangshu Zhang,Weixin Peng,Shruti Salunkhe,Madison Davis,Qinghua Song,Sara Beygi,Harry Miao,Mike Mattie,Rhine S Shen,Caron A Jacobson,Davide Bedognetti,Simone Filosto,Sattva S Neelapu","doi":"10.1172/jci181893","DOIUrl":"https://doi.org/10.1172/jci181893","url":null,"abstract":"BACKGROUNDAxicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B-cell lymphomas in the ZUMA-5 trial.METHODSHere, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 follicular lymphoma (FL) patients.RESULTSIn univariate and multivariate analyses, pre-treatment inflammatory markers, including TNFα and IL12p40, as well as total metabolic tumor volume (TMTV) associated with disease progression. Conversely, T-naïve-like product phenotype associated with improved outcome, particularly in high TMTV patients. These covariates improved risk stratification when combined with the FL International Prognostic Index. Post-infusion, CAR T-cell expansion associated with improved outcome, while serum inflammatory and immuno-modulatory markers, including TNFα associated with disease progression and occurrence of high-grade cytokine release syndrome or neurologic events, presenting targets to improve the therapeutic index of axi-cel in FL. Tumor gene expression profiling revealed that both type I and II IFN signaling associated with disease progression and higher expression of T cell exhaustion markers, including TIM3 and LAG3. Pre- or post-treatment CD19 expression on tumor was not associated with outcome.CONCLUSIONThese findings offer insights into mechanisms of resistance and toxicity, risk stratification, and strategies for development of next generation CAR-T approaches.TRIAL REGISTRATIONCLINICALTRIALSgov NCT03105336.FUNDINGKite, a Gilead Company.  .","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}