Journal of Clinical Investigation最新文献_第2页

APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer's disease.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI184656

Qiuyun Tian, Junjie Li, Bin Wu, Yayan Pang, Wenting He, Qian Xiao, Jiaojiao Wang, Lilin Yi, Na Tian, Xiuyu Shi, Lei Xia, Xin Tian, Mulan Chen, Yepeng Fan, Boqing Xu, Yuhan Tao, Weihong Song, Yehong Du, Zhifang Dong

{"title":"APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer's disease.","authors":"Qiuyun Tian, Junjie Li, Bin Wu, Yayan Pang, Wenting He, Qian Xiao, Jiaojiao Wang, Lilin Yi, Na Tian, Xiuyu Shi, Lei Xia, Xin Tian, Mulan Chen, Yepeng Fan, Boqing Xu, Yuhan Tao, Weihong Song, Yehong Du, Zhifang Dong","doi":"10.1172/JCI184656","DOIUrl":"10.1172/JCI184656","url":null,"abstract":"Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI183274

Tomonori Oka, Sabrina S Smith, Heehwa G Son, Truelian Lee, Valeria S Oliver-Garcia, Mahsa Mortaja, Kathryn E Trerice, Lily S Isakoff, Danielle N Conrad, Marjan Azin, Neel S Raval, Mary Tabacchi, Luni Emdad, Swadesh K Das, Paul B Fisher, Lynn A Cornelius, Shadmehr Demehri

{"title":"T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions.","authors":"Tomonori Oka, Sabrina S Smith, Heehwa G Son, Truelian Lee, Valeria S Oliver-Garcia, Mahsa Mortaja, Kathryn E Trerice, Lily S Isakoff, Danielle N Conrad, Marjan Azin, Neel S Raval, Mary Tabacchi, Luni Emdad, Swadesh K Das, Paul B Fisher, Lynn A Cornelius, Shadmehr Demehri","doi":"10.1172/JCI183274","DOIUrl":"10.1172/JCI183274","url":null,"abstract":"The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus-5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus-5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A conversation with Zhijian (James) Chen.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI189543

Ushma S Neill

引用次数: 0

Mechanisms of postischemic cardiac death and protection following myocardial injury.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI184134

Yusuf Mastoor, Elizabeth Murphy, Barbara Roman

{"title":"Mechanisms of postischemic cardiac death and protection following myocardial injury.","authors":"Yusuf Mastoor, Elizabeth Murphy, Barbara Roman","doi":"10.1172/JCI184134","DOIUrl":"10.1172/JCI184134","url":null,"abstract":"Acute myocardial infarction (MI) is a leading cause of death worldwide. Although with current treatment, acute mortality from MI is low, the damage and remodeling associated with MI are responsible for subsequent heart failure. Reducing cell death associated with acute MI would decrease the mortality associated with heart failure. Despite considerable study, the precise mechanism by which ischemia and reperfusion (I/R) trigger cell death is still not fully understood. In this Review, we summarize the changes that occur during I/R injury, with emphasis on those that might initiate cell death, such as calcium overload and oxidative stress. We review cell-death pathways and pathway crosstalk and discuss cardioprotective approaches in order to provide insight into mechanisms that could be targeted with therapeutic interventions. Finally, we review cardioprotective clinical trials, with a focus on possible reasons why they were not successful. Cardioprotection has largely focused on inhibiting a single cell-death pathway or one death-trigger mechanism (calcium or ROS). In treatment of other diseases, such as cancer, the benefit of targeting multiple pathways with a \"drug cocktail\" approach has been demonstrated. Given the crosstalk between cell-death pathways, targeting multiple cardiac death mechanisms should be considered.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preexisting vaccine-primed heterosubtypic T cell immunity protects the maternal-fetal unit from adverse influenza outcomes in mice.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI179230

Valeria Flores Malavet, Kunal Dhume, Ali Satchmei, Andrea C Arvelo, Aaron J Beaird, Siva N Annamalai, Lauren A Kimball, K Kai McKinstry, Tara M Strutt

{"title":"Preexisting vaccine-primed heterosubtypic T cell immunity protects the maternal-fetal unit from adverse influenza outcomes in mice.","authors":"Valeria Flores Malavet, Kunal Dhume, Ali Satchmei, Andrea C Arvelo, Aaron J Beaird, Siva N Annamalai, Lauren A Kimball, K Kai McKinstry, Tara M Strutt","doi":"10.1172/JCI179230","DOIUrl":"10.1172/JCI179230","url":null,"abstract":"The risk of severe outcomes of influenza increases during pregnancy. Whether vaccine-induced T cell memory-primed prepregnancy retains the ability to mediate protection during pregnancy, when systemic levels of several hormones with putative immunomodulatory functions are increased, is unknown. Here, using murine adoptive transfer systems and a translationally relevant model of cold-adapted live-attenuated influenza A virus vaccination, we show that preexisting virus-specific memory T cell responses are largely unaltered and highly protective against heterotypic viral challenges during pregnancy. Expression of the transcription factor T-bet, which is upregulated in antiviral T cells responding in pregnant mice, is critical in preventing hormone-associated gain of detrimental T helper type 2 (TH2) attributes reported in other settings. Beyond antiviral effects, preexisting vaccine-primed T cell immunity prevents metabolic dysfunction in gravid dams and adverse neonatal outcomes often associated with maternal influenza infection. These results demonstrate robust protection of the maternal-fetal unit from severe consequences of respiratory virus infection by preexisting T cell immunity.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TGF-β drives differentiation of intraepithelial mast cells in inflamed airway mucosa.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI186337

Axel Roers

引用次数: 0

FOXO1 pathway activation by VISTA immune checkpoint restrains pulmonary ILC2 functions.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI184932

Mohammad Hossein Kazemi, Zahra Momeni-Varposhti, Xin Li, Benjamin P Hurrell, Yoshihiro Sakano, Stephen Shen, Pedram Shafiei-Jahani, Kei Sakano, Omid Akbari

{"title":"FOXO1 pathway activation by VISTA immune checkpoint restrains pulmonary ILC2 functions.","authors":"Mohammad Hossein Kazemi, Zahra Momeni-Varposhti, Xin Li, Benjamin P Hurrell, Yoshihiro Sakano, Stephen Shen, Pedram Shafiei-Jahani, Kei Sakano, Omid Akbari","doi":"10.1172/JCI184932","DOIUrl":"https://doi.org/10.1172/JCI184932","url":null,"abstract":"Type-2 innate lymphoid cells (ILC2s) play a pivotal role in the development of airway hyperreactivity (AHR). However, the regulatory mechanisms governing ILC2 function remain inadequately explored. This study uncovers V-domain Ig suppressor of T cell activation (VISTA) as an inhibitory immune checkpoint crucial for modulating ILC2-driven lung inflammation. VISTA is upregulated in activated pulmonary ILC2s and plays a key role in regulating lung inflammation, as VISTA-deficient ILC2s demonstrate increased proliferation and function, resulting in elevated type-2 cytokine production and exacerbation of AHR. Mechanistically, VISTA stimulation activates Forkhead box O1 (FOXO1), leading to modulation of ILC2 proliferation and function. The suppressive effects of FOXO1 on ILC2 effector function were confirmed using FOXO1 inhibitors and activators. Moreover, VISTA-deficient ILC2s exhibit enhanced fatty acid oxidation and oxidative phosphorylation to meet their high energy demands. Therapeutically, VISTA agonist treatment reduces ILC2 function both ex vivo and in vivo, significantly alleviating ILC2-driven AHR. Our murine findings were validated in human ILC2s, where a VISTA agonist reduces their function ex vivo and in a humanized mouse model of ILC2-driven AHR. Our studies unravel VISTA as an immune checkpoint for ILC2 regulation via the FOXO1 pathway, presenting potential therapeutic strategies for allergic asthma by modulating ILC2 responses.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI183836

James P Bridges, Eszter K Vladar, Jonathan S Kurche, Andrei Krivoi, Ian T Stancil, Evgenia Dobrinskikh, Yan Hu, Sarah K Sasse, Joyce S Lee, Rachel Z Blumhagen, Ivana V Yang, Anthony N Gerber, Anna L Peljto, Christopher M Evans, Elizabeth F Redente, David Wh Riches, David A Schwartz

{"title":"Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium.","authors":"James P Bridges, Eszter K Vladar, Jonathan S Kurche, Andrei Krivoi, Ian T Stancil, Evgenia Dobrinskikh, Yan Hu, Sarah K Sasse, Joyce S Lee, Rachel Z Blumhagen, Ivana V Yang, Anthony N Gerber, Anna L Peljto, Christopher M Evans, Elizabeth F Redente, David Wh Riches, David A Schwartz","doi":"10.1172/JCI183836","DOIUrl":"10.1172/JCI183836","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDAreceptor antibody encephalitis mouse model.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-31 DOI: 10.1172/JCI173493

Jing Zhou, Ariele L Greenfield, Rita P Loudermilk, Christopher M Bartley, Chun Chen, Xiumin Chen, Morgane Ah Leroux, Yujun Lu, Deanna Necula, Thomas T Ngo, Baouyen T Tran, Patrick S Honma, Kelli Lauderdale, Chao Zhao, Xiaoyuan Zhou, Hong Wang, Roger A Nicoll, Cong Wang, Jeanne T Paz, Jorge J Palop, Michael R Wilson, Samuel J Pleasure

{"title":"Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDAreceptor antibody encephalitis mouse model.","authors":"Jing Zhou, Ariele L Greenfield, Rita P Loudermilk, Christopher M Bartley, Chun Chen, Xiumin Chen, Morgane Ah Leroux, Yujun Lu, Deanna Necula, Thomas T Ngo, Baouyen T Tran, Patrick S Honma, Kelli Lauderdale, Chao Zhao, Xiaoyuan Zhou, Hong Wang, Roger A Nicoll, Cong Wang, Jeanne T Paz, Jorge J Palop, Michael R Wilson, Samuel J Pleasure","doi":"10.1172/JCI173493","DOIUrl":"https://doi.org/10.1172/JCI173493","url":null,"abstract":"NMDA receptor mediated autoimmune encephalitis (NMDAR-AE) frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long- term effects of exposure to a patient-derived GluN1-specific monoclonal antibody (mAb) during a critical developmental period (from postnatal day 3 to day 12) in mice. We observed long-lasting sensory-motor deficits characteristic of NMDAR-AE, along with permanent changes in callosal axons within the primary somatosensory cortex (S1) in adulthood, including increased terminal branch complexity. This complexity was associated with paroxysmal recruitment of neurons in S1 in response to callosal stimulation. Particularly during complex motor tasks, mAb3-treated mice exhibited significantly reduced inter-hemispheric functional connectivity between S1 regions, consistent with pronounced sensory-motor behavioral deficits. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons, which could significantly impair sensory-motor integration and contribute to long-lasting sensory-motor deficits. Our study establishes a new model of NMDAR-AE and identifies novel cellular and network-level mechanisms underlying persistent sensory-motor deficits in this context. These insights lay the foundation for future research into molecular mechanisms and the development of targeted therapeutic interventions.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-31 DOI: 10.1172/JCI183671

Xiang Xiao, Yong Du, Si Sun, Xiaojun Su, Junji Xing, Guangchuan Wang, Steven M Elzein, Dawei Zou, Laurie J Minze, Zhuyun Mao, Rafik M Ghobrial, Ashton A Connor, Wenhao Chen, Zhiqiang Zhang, Xian C Li

{"title":"Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models.","authors":"Xiang Xiao, Yong Du, Si Sun, Xiaojun Su, Junji Xing, Guangchuan Wang, Steven M Elzein, Dawei Zou, Laurie J Minze, Zhuyun Mao, Rafik M Ghobrial, Ashton A Connor, Wenhao Chen, Zhiqiang Zhang, Xian C Li","doi":"10.1172/JCI183671","DOIUrl":"https://doi.org/10.1172/JCI183671","url":null,"abstract":"T cells have a remarkable capacity to clonally expand, a process that is intricately linked to their effector activities. As vigorously proliferating T cell also incur substantial DNA lesions, how the dividing T cells safeguard their genomic integrity to allow the generation of T effector cells remains largely unknown. Here we report the identification of the apurinic/apyrimidinic endonuclease-1 (Apex1) as an indispensable molecule for the induction of cytopathic T effectors in mouse models. We demonstrate that conditional deletion of Apex1 in T cells results in a remarkable accumulation of baseless DNA sites in the genome of proliferating T cells, which further leads to genomic instability and apoptotic cell death. Consequently, Apex1-deleted T cells fail to acquire any effector features after activation and fail to mediate autoimmune diseases and allergic tissue damages. Detailed mutational analyses pinpoint the importance of its endonuclease domain in the generation of T effector cells. We provide further evidence that inhibiting the base repair activities of Apex1 with chemical inhibitors similarly abrogates the induction of autoimmune diseases. Collectively, our study suggests that Apex1 serves as a gatekeeper for the generation of cytopathic T cells and that therapeutically targeting Apex1 may have important clinical implications in the treatment of autoimmune diseases.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0