首页 > 最新文献

Journal of Clinical Investigation最新文献

英文 中文
Single-nuclei transcriptomics reveals TBX5-dependent targets in a patient with Holt-Oram syndrome. 单核转录组学揭示了一名霍尔特-奥拉姆综合征患者的 TBX5 依赖性靶点。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-14 DOI: 10.1172/JCI180670
Jeffrey D Steimle, Yi Zhao, Fansen Meng, Mikaela E Taylor, Diwakar Turaga, Iki Adachi, Xiao Li, James F Martin
{"title":"Single-nuclei transcriptomics reveals TBX5-dependent targets in a patient with Holt-Oram syndrome.","authors":"Jeffrey D Steimle, Yi Zhao, Fansen Meng, Mikaela E Taylor, Diwakar Turaga, Iki Adachi, Xiao Li, James F Martin","doi":"10.1172/JCI180670","DOIUrl":"https://doi.org/10.1172/JCI180670","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621123","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
Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13+ CD8+ T-cells. 扁平苔藓对巴利替尼的快速反应与细胞毒性 CXCL13+ CD8+ T 细胞的抑制有关。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-14 DOI: 10.1172/JCI179436
Angelina S Hwang, Jacob A Kechter, Tran H Do, Alysia N Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M Brumfiel, Meera H Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L Yousif, Alyssa L Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J Michelle Kahlenberg, Allison C Billi, Olesya Plazyo, Lam C Tsoi, Mark R Pittelkow, Johann E Gudjonsson, Aaron R Mangold

Background: Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon gamma (IFN)-γ, a cytokine implicated in the pathogenesis of LP.

Methods: In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and post-treatment samples.

Results: An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis.

Conclusion: This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP.

Trial registration: NCT05188521.ROLE OF FUNDING SOURCE. Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.

背景:皮肤扁平苔藓(LP)是一种顽固的、难以治疗的炎症性皮肤病,其特征是皮肤上出现瘙痒的、平顶的、剧烈的丘疹。巴利昔尼是一种口服 Janus 激酶(JAK)1/2 抑制剂,可干扰γ干扰素(IFN)-γ 的信号通路,而γ干扰素是一种细胞因子,与 LP 的发病机制有关:在这项II期试验中,12名皮肤型红斑狼疮患者每天接受2毫克巴利替尼治疗,为期16周,同时对治疗前后的样本进行了深入的空间、单细胞和大体转录组学分析:患者出现了早期和持续的临床反应,83.3%的患者在第16周时出现反应。我们的分子数据确定了 LP 皮肤中独特的寡克隆 IFN-γ、CD8+、CXCL13+ 细胞毒性 T 细胞群,并证明在治疗 2 周内 IFN 特征迅速下降,在表皮基底层最为显著:这项研究证明了 JAK 抑制剂对 LP 的疗效和分子机制:NCT05188521.role of funding source.Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.
{"title":"Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13+ CD8+ T-cells.","authors":"Angelina S Hwang, Jacob A Kechter, Tran H Do, Alysia N Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M Brumfiel, Meera H Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L Yousif, Alyssa L Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J Michelle Kahlenberg, Allison C Billi, Olesya Plazyo, Lam C Tsoi, Mark R Pittelkow, Johann E Gudjonsson, Aaron R Mangold","doi":"10.1172/JCI179436","DOIUrl":"https://doi.org/10.1172/JCI179436","url":null,"abstract":"<p><strong>Background: </strong>Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon gamma (IFN)-γ, a cytokine implicated in the pathogenesis of LP.</p><p><strong>Methods: </strong>In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and post-treatment samples.</p><p><strong>Results: </strong>An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis.</p><p><strong>Conclusion: </strong>This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP.</p><p><strong>Trial registration: </strong>NCT05188521.ROLE OF FUNDING SOURCE. Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621108","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
Complement-producing maternal microchimeric cells override infection susceptibility in complement-deficient murine offspring. 产生补体的母体微嵌合细胞可克服补体缺陷小鼠后代的感染易感性。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-14 DOI: 10.1172/JCI187001
Giang Pham, Raymond E Diep, Lucien H Turner, David B Haslam, Sing Sing Way
{"title":"Complement-producing maternal microchimeric cells override infection susceptibility in complement-deficient murine offspring.","authors":"Giang Pham, Raymond E Diep, Lucien H Turner, David B Haslam, Sing Sing Way","doi":"10.1172/JCI187001","DOIUrl":"https://doi.org/10.1172/JCI187001","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621034","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
MAP3K1 mutations confer tumor immune heterogeneity in hormone receptor-positive HER2-negative breast cancer. MAP3K1 突变使激素受体阳性 HER2 阴性乳腺癌具有肿瘤免疫异质性。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-12 DOI: 10.1172/JCI183656
Yuwen Cai, Cui-Cui Liu, Yanwu Zhang, Yiming Liu, Lie Chen, Xin Xiong, Zhiming Shao, Ke-Da Yu

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the most common type of breast cancer, is facing challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2- breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of HR+/HER2- breast cancer patients (n = 351) and revealed that HR+/HER2- breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2- breast cancer was related to MAP3K1 mutation and we validated experimentally that MAP3K1 mutation could attenuate CD8+ T cell-mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I-mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNAs, thereby driving tumor immune escape. In preclinical models, the postbiotics tyramine could reverse the MAP3K1 mutation-induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy. Collectively, our study identified the vital biomarker driving the immunological heterogeneity of HR+/HER2- breast cancer and elucidated the underlying molecular mechanisms, which provided the promise of tyramine as a novel therapeutic strategy to enhance the efficacy of immunotherapy.

激素受体阳性(HR+)/人表皮生长因子受体 2 阴性(HER2-)乳腺癌是最常见的乳腺癌类型,目前正面临着内分泌治疗耐药和远处复发等挑战。免疫疗法在治疗三阴性乳腺癌方面取得了进展,但对HR+/HER2-乳腺癌的免疫学研究仍处于早期阶段。在此,我们对一大批HR+/HER2-乳腺癌患者(n = 351)进行了多组学分析,发现HR+/HER2-乳腺癌具有高度异质性的肿瘤免疫微环境。值得注意的是,HR+/HER2-乳腺癌的免疫异质性与MAP3K1突变有关,我们通过实验验证了MAP3K1突变可削弱CD8+ T细胞介导的抗肿瘤免疫。从机理上讲,MAP3K1突变通过促进抗原肽转运体1/2(TAP1/2)mRNA的降解,抑制了MHC-I介导的肿瘤抗原呈递,从而推动了肿瘤免疫逃逸。在临床前模型中,后生化药物酪胺能逆转MAP3K1突变诱导的MHC-I减少,从而提高免疫疗法的疗效。总之,我们的研究发现了驱动HR+/HER2-乳腺癌免疫异质性的重要生物标志物,并阐明了其潜在的分子机制,为泰乐菌素作为一种新型治疗策略提高免疫疗法的疗效提供了希望。
{"title":"MAP3K1 mutations confer tumor immune heterogeneity in hormone receptor-positive HER2-negative breast cancer.","authors":"Yuwen Cai, Cui-Cui Liu, Yanwu Zhang, Yiming Liu, Lie Chen, Xin Xiong, Zhiming Shao, Ke-Da Yu","doi":"10.1172/JCI183656","DOIUrl":"https://doi.org/10.1172/JCI183656","url":null,"abstract":"<p><p>Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the most common type of breast cancer, is facing challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2- breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of HR+/HER2- breast cancer patients (n = 351) and revealed that HR+/HER2- breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2- breast cancer was related to MAP3K1 mutation and we validated experimentally that MAP3K1 mutation could attenuate CD8+ T cell-mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I-mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNAs, thereby driving tumor immune escape. In preclinical models, the postbiotics tyramine could reverse the MAP3K1 mutation-induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy. Collectively, our study identified the vital biomarker driving the immunological heterogeneity of HR+/HER2- breast cancer and elucidated the underlying molecular mechanisms, which provided the promise of tyramine as a novel therapeutic strategy to enhance the efficacy of immunotherapy.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621038","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
Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging. 烟酰胺和吡哆醇能刺激肌肉干细胞扩张,增强衰老过程中的再生能力。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-12 DOI: 10.1172/JCI163648
Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E Jacot, Thibaut Desgeorges, José-Luis Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N Feige

Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.

骨骼肌的生长和修复依赖于常驻肌肉干细胞(MuSCs)。衰老和肌肉疾病会损害肌肉干细胞的功能,导致干细胞衰竭和再生能力下降,从而造成骨骼肌质量和力量的逐渐丧失。由于临床上缺乏专门针对肌肉干细胞的营养解决方案,我们利用人体肌原性祖细胞(hMP)对食物中的天然分子进行了高含量成像筛选,发现烟酰胺(NAM)和吡哆醇(PN)是具有生物活性的营养素,可刺激肌肉干细胞,并具有安全的人类使用史。NAM和PN通过CK1介导的细胞质β-catenin激活和AKT信号传导协同作用,促进MuSCs的扩增和分化。口服 NAM/PN 组合疗法可通过刺激肌肉干细胞加速体内肌肉再生,在恢复过程中增强肌肉力量,并克服衰老过程中肌肉干细胞的功能障碍和再生失败。在模型生物体中,NAM 和生物活性 PN 的水平会在衰老过程中自发下降,而在 186 名老年人组成的人类队列中,NAM 和生物活性 PN 的水平与肌肉质量和行走速度相互依存。总之,我们的研究结果确立了 NAM/PN 作为一种新的营养干预措施的地位,它能刺激肌肉干细胞、促进肌肉再生、缓解与年龄相关的肌肉衰退,并有机会直接应用于临床。
{"title":"Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.","authors":"Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E Jacot, Thibaut Desgeorges, José-Luis Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N Feige","doi":"10.1172/JCI163648","DOIUrl":"https://doi.org/10.1172/JCI163648","url":null,"abstract":"<p><p>Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621107","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
In utero human cytomegalovirus infection expands NK-like FcγRIII+ CD8+ T cells that mediate Fc antibody functions. 宫内人类巨细胞病毒感染可扩增 NK 样 FcγRIII+ CD8+ T 细胞,从而介导 Fc 抗体功能。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-12 DOI: 10.1172/JCI181342
Eleanor C Semmes, Danielle R Nettere, Ashley N Nelson, Jillian H Hurst, Derek W Cain, Trevor D Burt, Joanne Kurtzberg, R Keith Reeves, Carolyn B Coyne, Genevieve G Fouda, Justin Pollara, Sallie R Permar, Kyle M Walsh

Human cytomegalovirus (HCMV) profoundly impacts host T and natural killer (NK) cells across the lifespan, yet how this common congenital infection modulates developing fetal immune cell compartments remains underexplored. Using cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells following HCMV exposure in utero. Most FcγRIII+ CD8+ T cells express the canonical αβ T cell receptor (TCR) but a proportion express non-canonical γδ TCR. FcγRIII+ CD8+ T cells are highly differentiated and have increased expression of NK cell markers and cytolytic molecules. Transcriptional analysis reveals FcγRIII+ CD8+ T cells upregulate T-bet and downregulate BCL11B, known transcription factors that govern T/NK cell fate. We show that FcγRIII+ CD8+ T cells mediate antibody-dependent IFNγ production and degranulation against IgG-opsonized target cells, similar to NK cell antibody-dependent cellular cytotoxicity (ADCC). FcγRIII+ CD8+ T cell Fc effector functions were further enhanced by interleukin-15 (IL-15), as has been observed in neonatal NK cells. Our study reveals that FcγRIII+ CD8+ T cells elicited in utero by HCMV infection can execute Fc-mediated effector functions bridging cellular and humoral immunity and may be a promising target for antibody-based therapeutics and vaccination in early life.

人类巨细胞病毒(HCMV)对宿主T细胞和自然杀伤(NK)细胞的整个生命周期都有深远影响,但这种常见的先天性感染如何调节发育中的胎儿免疫细胞区仍未得到充分探索。利用先天性 HCMV(cCMV)感染和未感染 HCMV 的新生儿的脐带血,我们发现宫内 HCMV 暴露后,表达 Fcγ 受体 III(FcγRIII)的 CD8+ T 细胞扩增。大多数 FcγRIII+ CD8+ T 细胞表达规范的 αβ T 细胞受体(TCR),但也有一部分表达非规范的 γδ TCR。FcγRIII+ CD8+ T细胞高度分化,NK细胞标记和细胞溶解分子的表达增加。转录分析表明,FcγRIII+ CD8+ T细胞上调T-bet,下调BCL11B,而BCL11B是已知的能控制T/NK细胞命运的转录因子。我们的研究表明,FcγRIII+ CD8+ T细胞介导了抗体依赖性 IFNγ 的产生和针对 IgG 冲溶靶细胞的脱颗粒作用,类似于 NK 细胞的抗体依赖性细胞毒性(ADCC)。FcγRIII+ CD8+ T细胞的Fc效应功能在白细胞介素-15(IL-15)的作用下进一步增强,这一点在新生儿NK细胞中也已观察到。我们的研究揭示了 HCMV 感染在子宫内诱导的 FcγRIII+ CD8+ T 细胞能执行 Fc 介导的效应功能,在细胞免疫和体液免疫之间架起桥梁,可能是生命早期抗体疗法和疫苗接种的一个有前途的靶点。
{"title":"In utero human cytomegalovirus infection expands NK-like FcγRIII+ CD8+ T cells that mediate Fc antibody functions.","authors":"Eleanor C Semmes, Danielle R Nettere, Ashley N Nelson, Jillian H Hurst, Derek W Cain, Trevor D Burt, Joanne Kurtzberg, R Keith Reeves, Carolyn B Coyne, Genevieve G Fouda, Justin Pollara, Sallie R Permar, Kyle M Walsh","doi":"10.1172/JCI181342","DOIUrl":"10.1172/JCI181342","url":null,"abstract":"<p><p>Human cytomegalovirus (HCMV) profoundly impacts host T and natural killer (NK) cells across the lifespan, yet how this common congenital infection modulates developing fetal immune cell compartments remains underexplored. Using cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells following HCMV exposure in utero. Most FcγRIII+ CD8+ T cells express the canonical αβ T cell receptor (TCR) but a proportion express non-canonical γδ TCR. FcγRIII+ CD8+ T cells are highly differentiated and have increased expression of NK cell markers and cytolytic molecules. Transcriptional analysis reveals FcγRIII+ CD8+ T cells upregulate T-bet and downregulate BCL11B, known transcription factors that govern T/NK cell fate. We show that FcγRIII+ CD8+ T cells mediate antibody-dependent IFNγ production and degranulation against IgG-opsonized target cells, similar to NK cell antibody-dependent cellular cytotoxicity (ADCC). FcγRIII+ CD8+ T cell Fc effector functions were further enhanced by interleukin-15 (IL-15), as has been observed in neonatal NK cells. Our study reveals that FcγRIII+ CD8+ T cells elicited in utero by HCMV infection can execute Fc-mediated effector functions bridging cellular and humoral immunity and may be a promising target for antibody-based therapeutics and vaccination in early life.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621035","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
Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice. 炎症串扰损害吞噬受体,加重小鼠克隆造血的动脉粥样硬化。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-12 DOI: 10.1172/JCI182939
Wenli Liu, Brian D Hardaway, Eunyoung Kim, Jessica Pauli, Justus Leonard Wettich, Mustafa Yalcinkaya, Cheng-Chieh Hsu, Tong Xiao, Muredach P Reilly, Ira Tabas, Lars Maegdefessel, Kai Schlepckow, Haass Christian, Nan Wang, Alan R Tall

Clonal hematopoiesis (CH) increases inflammasome-linked atherosclerosis but the mechanisms by which CH mutant cells transmit inflammatory signals to non-mutant cells are largely unknown. To address this question we transplanted 1.5% Jak2VF bone marrow (BM) cells with 98.5% WT BM cells into hyperlipidemic Ldlr-/- mice. Low allele burden (LAB) mice showed accelerated atherosclerosis with increased features of plaque instability, decreased levels of macrophage phagocytic receptors MERTK and TREM2, and increased neutrophil extracellular traps (NETs). These changes were reversed when Jak2VF BM was transplanted with Il1r1-/- BM. LAB mice with non-cleavable MERTK in WT BM showed improvements in necrotic core and fibrous cap formation and reduced NETs. An agonistic TREM2 antibody (4D9) markedly increased fibrous caps in both control and LAB mice eliminating the difference between groups. Mechanistically, 4D9 increased TREM2+PDGFB+ macrophages and PDGF receptor-α positive fibroblast-like cells in the cap region. TREM2 and PDGFB mRNA levels were positively correlated in human carotid plaques and co-expressed in macrophages. In summary, low frequency Jak2VF mutations promote atherosclerosis via IL-1 signaling from Jak2VF to WT macrophages and neutrophils promoting cleavage of phagocytic receptors and features of plaque instability. Therapeutic approaches that stabilize MERTK or TREM2 could promote plaque stabilization especially in CH- and inflammasome-driven atherosclerosis.

克隆造血(CH)会增加与炎症体相关的动脉粥样硬化,但CH突变细胞向非突变细胞传递炎症信号的机制在很大程度上是未知的。为了解决这个问题,我们将1.5%的Jak2VF骨髓(BM)细胞和98.5%的WT骨髓(BM)细胞移植到高脂血症Ldlr-/-小鼠体内。低等位基因负荷(LAB)小鼠表现出动脉粥样硬化加速,斑块不稳定性增加,巨噬细胞吞噬受体 MERTK 和 TREM2 水平下降,中性粒细胞胞外陷阱(NET)增加。用 Il1r1-/- BM 移植 Jak2VF BM 可逆转这些变化。WT BM 中的 MERTK 不可清除的 LAB 小鼠在坏死核心和纤维帽形成方面有所改善,NET 也有所减少。激动剂 TREM2 抗体(4D9)显著增加了对照组和 LAB 小鼠的纤维帽,消除了组间差异。从机制上讲,4D9 增加了纤维帽区域的 TREM2+PDGFB+ 巨噬细胞和 PDGF 受体-α 阳性成纤维细胞。在人类颈动脉斑块中,TREM2 和 PDGFB mRNA 水平呈正相关,并在巨噬细胞中共同表达。总之,低频 Jak2VF 突变通过从 Jak2VF 向 WT 巨噬细胞和中性粒细胞传递 IL-1 信号,促进吞噬受体的裂解和斑块的不稳定性特征,从而促进动脉粥样硬化。稳定MERTK或TREM2的治疗方法可促进斑块稳定,尤其是在CH和炎性体驱动的动脉粥样硬化中。
{"title":"Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice.","authors":"Wenli Liu, Brian D Hardaway, Eunyoung Kim, Jessica Pauli, Justus Leonard Wettich, Mustafa Yalcinkaya, Cheng-Chieh Hsu, Tong Xiao, Muredach P Reilly, Ira Tabas, Lars Maegdefessel, Kai Schlepckow, Haass Christian, Nan Wang, Alan R Tall","doi":"10.1172/JCI182939","DOIUrl":"https://doi.org/10.1172/JCI182939","url":null,"abstract":"<p><p>Clonal hematopoiesis (CH) increases inflammasome-linked atherosclerosis but the mechanisms by which CH mutant cells transmit inflammatory signals to non-mutant cells are largely unknown. To address this question we transplanted 1.5% Jak2VF bone marrow (BM) cells with 98.5% WT BM cells into hyperlipidemic Ldlr-/- mice. Low allele burden (LAB) mice showed accelerated atherosclerosis with increased features of plaque instability, decreased levels of macrophage phagocytic receptors MERTK and TREM2, and increased neutrophil extracellular traps (NETs). These changes were reversed when Jak2VF BM was transplanted with Il1r1-/- BM. LAB mice with non-cleavable MERTK in WT BM showed improvements in necrotic core and fibrous cap formation and reduced NETs. An agonistic TREM2 antibody (4D9) markedly increased fibrous caps in both control and LAB mice eliminating the difference between groups. Mechanistically, 4D9 increased TREM2+PDGFB+ macrophages and PDGF receptor-α positive fibroblast-like cells in the cap region. TREM2 and PDGFB mRNA levels were positively correlated in human carotid plaques and co-expressed in macrophages. In summary, low frequency Jak2VF mutations promote atherosclerosis via IL-1 signaling from Jak2VF to WT macrophages and neutrophils promoting cleavage of phagocytic receptors and features of plaque instability. Therapeutic approaches that stabilize MERTK or TREM2 could promote plaque stabilization especially in CH- and inflammasome-driven atherosclerosis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621037","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
68Ga-MY6349 PET/CT imaging to assess Trop2 expression in multiple types of cancer. 68Ga-MY6349 PET/CT 成像评估多种癌症中 Trop2 的表达。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-07 DOI: 10.1172/JCI185408
Haojun Chen, Liang Zhao, Yizhen Pang, Jiyun Shi, Hannan Gao, Yining Sun, Jianhao Chen, Hao Fu, Jiayu Cai, Lingyu Yu, Ru Zeng, Long Sun, Hua Wu, Zhanxiang Wang, Fan Wang

Background Considering trophoblast cell surface antigen 2 (Trop2) is overexpressed in a wide range of human epithelial cancers, it presents an attractive target for the diagnosis and treatment of multiple types of cancer. Herein, we have developed a Trop2-specific radiotracer, 68Ga-MY6349, and present a prospective, investigator-initiated trial to explore the clinical values of 68Ga-MY6349 PET/CT. Methods In this translational study, 90 patients with 15 types of cancer, who underwent 68Ga-MY6349 PET/CT, were enrolled prospectively. Among them, 78 patients underwent paired 68Ga-MY6349 and 18F-FDG PET/CT, and 12 patients with prostate cancer underwent paired 68Ga-MY6349 and 68Ga-PSMA-11 PET/CT. Results Among the 90 patients across 15 types of cancer, 68Ga-MY6349 uptake in tumors was generally high but heterogeneous, varying among lesions, patients, and cancer types. Trop2 expression level determined by immunohistochemistry was highly correlated with 68Ga-MY6349 uptake at primary and metastatic tumor sites. 68Ga-MY6349 PET/CT showed higher tumor uptake (quantified by SUVmax) than 18F-FDG PET/CT in certain types of cancer, including breast (7.2 vs. 5.4, P < 0.001), prostate (9.2 vs. 3.0, P < 0.001), and thyroid cancers (8.5 vs. 3.7, P < 0.001). When compared with 68Ga-PSMA-11, 68Ga-MY6349 PET/CT exhibited comparable lesion uptake (12.2 vs. 12.5, P = 0.223) but a better tumor-to-background contrast (15.8 vs. 12.2, P < 0.001) for primary and metastatic prostate cancer, allowing visualization of more metastatic lesions. Conclusion 68Ga-MY6349 PET/CT is a non-invasive method for comprehensively assessing Trop2 expression in tumors, which can improve the diagnosis and staging for cancer patients, and aid in the decision-making for Trop2-targeted therapies and advancing personalized treatment.

背景 考虑到滋养层细胞表面抗原 2(Trop2)在多种人类上皮癌中过度表达,它为多种类型癌症的诊断和治疗提供了一个极具吸引力的靶点。在此,我们开发了一种 Trop2 特异性放射性示踪剂 68Ga-MY6349,并提出了一项由研究者发起的前瞻性试验,以探索 68Ga-MY6349 PET/CT 的临床价值。方法 在这项转化研究中,前瞻性地纳入了 90 名接受 68Ga-MY6349 PET/CT 检查的 15 种癌症患者。其中,78 名患者接受了 68Ga-MY6349 和 18F-FDG PET/CT 配对检查,12 名前列腺癌患者接受了 68Ga-MY6349 和 68Ga-PSMA-11 PET/CT 配对检查。结果 在 15 种癌症类型的 90 名患者中,68Ga-MY6349 在肿瘤中的摄取量普遍较高,但在病灶、患者和癌症类型之间存在差异。免疫组化确定的 Trop2 表达水平与原发性和转移性肿瘤部位的 68Ga-MY6349 摄取高度相关。在某些类型的癌症中,68Ga-MY6349 PET/CT 比 18F-FDG PET/CT 显示出更高的肿瘤摄取率(以 SUVmax 定量),包括乳腺癌(7.2 对 5.4,P < 0.001)、前列腺癌(9.2 对 3.0,P < 0.001)和甲状腺癌(8.5 对 3.7,P < 0.001)。与 68Ga-PSMA-11 相比,68Ga-MY6349 PET/CT 对原发性和转移性前列腺癌的病灶摄取率相当(12.2 对 12.5,P = 0.223),但肿瘤与背景的对比度更高(15.8 对 12.2,P < 0.001),可观察到更多的转移性病灶。结论 68Ga-MY6349 PET/CT 是一种全面评估肿瘤中 Trop2 表达的无创方法,可改善癌症患者的诊断和分期,有助于 Trop2 靶向疗法的决策和推进个性化治疗。
{"title":"68Ga-MY6349 PET/CT imaging to assess Trop2 expression in multiple types of cancer.","authors":"Haojun Chen, Liang Zhao, Yizhen Pang, Jiyun Shi, Hannan Gao, Yining Sun, Jianhao Chen, Hao Fu, Jiayu Cai, Lingyu Yu, Ru Zeng, Long Sun, Hua Wu, Zhanxiang Wang, Fan Wang","doi":"10.1172/JCI185408","DOIUrl":"https://doi.org/10.1172/JCI185408","url":null,"abstract":"<p><p>Background Considering trophoblast cell surface antigen 2 (Trop2) is overexpressed in a wide range of human epithelial cancers, it presents an attractive target for the diagnosis and treatment of multiple types of cancer. Herein, we have developed a Trop2-specific radiotracer, 68Ga-MY6349, and present a prospective, investigator-initiated trial to explore the clinical values of 68Ga-MY6349 PET/CT. Methods In this translational study, 90 patients with 15 types of cancer, who underwent 68Ga-MY6349 PET/CT, were enrolled prospectively. Among them, 78 patients underwent paired 68Ga-MY6349 and 18F-FDG PET/CT, and 12 patients with prostate cancer underwent paired 68Ga-MY6349 and 68Ga-PSMA-11 PET/CT. Results Among the 90 patients across 15 types of cancer, 68Ga-MY6349 uptake in tumors was generally high but heterogeneous, varying among lesions, patients, and cancer types. Trop2 expression level determined by immunohistochemistry was highly correlated with 68Ga-MY6349 uptake at primary and metastatic tumor sites. 68Ga-MY6349 PET/CT showed higher tumor uptake (quantified by SUVmax) than 18F-FDG PET/CT in certain types of cancer, including breast (7.2 vs. 5.4, P < 0.001), prostate (9.2 vs. 3.0, P < 0.001), and thyroid cancers (8.5 vs. 3.7, P < 0.001). When compared with 68Ga-PSMA-11, 68Ga-MY6349 PET/CT exhibited comparable lesion uptake (12.2 vs. 12.5, P = 0.223) but a better tumor-to-background contrast (15.8 vs. 12.2, P < 0.001) for primary and metastatic prostate cancer, allowing visualization of more metastatic lesions. Conclusion 68Ga-MY6349 PET/CT is a non-invasive method for comprehensively assessing Trop2 expression in tumors, which can improve the diagnosis and staging for cancer patients, and aid in the decision-making for Trop2-targeted therapies and advancing personalized treatment.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604940","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
Progranulin-dependent repair function of Regulatory T cells drive bone fracture healing. 调节性 T 细胞的 Progranulin 依赖性修复功能推动骨折愈合。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-07 DOI: 10.1172/JCI180679
Ruiying Chen, Xiaomeng Zhang, Bin Li, Maurizio S Tonetti, Yijie Yang, Yuan Li, Beilei Liu, Shujiao Qian, Yingxin Gu, Qingwen Wang, Kairui Mao, Hao Cheng, Hongchang Lai, Junyu Shi

Local immunoinflammatory events instruct skeletal stem cells (SSCs) to repair/regenerate bone after injury, but mechanisms are incompletely understood. We hypothesized that specialized Regulatory T (Treg) cells are necessary for bone repair and interact directly with SSCs through organ-specific messages. Both in human patients with bone fracture and mouse model of bone injury, we identified a bone injury-responding Treg subpopulation with bone-repair capacity marked by CCR8. Local production of CCL1 induced a massive migration of CCR8+ Treg cells from periphery to the injury site. Depending on secretion of progranulin (PGRN), a protein encoded by the granulin (Grn) gene, CCR8+ Treg cells supported the accumulation and osteogenic differentiation of SSCs, and thereby bone repair. Mechanistically, we revealed that CCL1 enhanced expression level of basic leucine zipper ATF-like transcription factor (BATF) in CCR8+ Treg cells, which bound to Grn promoter and increased Grn translational output and then PGRN secretion. Together, our work provides a new perspective in osteoimmunology and highlights possible ways of manipulating Treg cell signaling to enhance bone repair and regeneration.

局部免疫炎症事件指示骨骼干细胞(SSCs)在损伤后修复/再生骨骼,但其机制尚不完全清楚。我们假设,特化的调节性T(Treg)细胞是骨修复所必需的,并通过器官特异性信息与骨骼干细胞直接相互作用。在人类骨折患者和小鼠骨损伤模型中,我们都发现了一个骨损伤反应 Treg 亚群,它具有以 CCR8 标记的骨修复能力。局部产生的 CCL1 会诱导 CCR8+ Treg 细胞从外周向损伤部位大量迁移。CCR8+Treg细胞通过分泌由粒细胞素(Grn)基因编码的蛋白质原粒细胞素(PGRN),支持造骨干细胞的聚集和成骨分化,从而促进骨修复。从机理上讲,我们发现 CCL1 可提高 CCR8+ Treg 细胞中碱性亮氨酸拉链 ATF 样转录因子(BATF)的表达水平,BATF 与 Grn 启动子结合,增加 Grn 的翻译输出,进而增加 PGRN 的分泌。总之,我们的工作为骨免疫学提供了一个新的视角,并强调了操纵 Treg 细胞信号增强骨修复和再生的可能途径。
{"title":"Progranulin-dependent repair function of Regulatory T cells drive bone fracture healing.","authors":"Ruiying Chen, Xiaomeng Zhang, Bin Li, Maurizio S Tonetti, Yijie Yang, Yuan Li, Beilei Liu, Shujiao Qian, Yingxin Gu, Qingwen Wang, Kairui Mao, Hao Cheng, Hongchang Lai, Junyu Shi","doi":"10.1172/JCI180679","DOIUrl":"https://doi.org/10.1172/JCI180679","url":null,"abstract":"<p><p>Local immunoinflammatory events instruct skeletal stem cells (SSCs) to repair/regenerate bone after injury, but mechanisms are incompletely understood. We hypothesized that specialized Regulatory T (Treg) cells are necessary for bone repair and interact directly with SSCs through organ-specific messages. Both in human patients with bone fracture and mouse model of bone injury, we identified a bone injury-responding Treg subpopulation with bone-repair capacity marked by CCR8. Local production of CCL1 induced a massive migration of CCR8+ Treg cells from periphery to the injury site. Depending on secretion of progranulin (PGRN), a protein encoded by the granulin (Grn) gene, CCR8+ Treg cells supported the accumulation and osteogenic differentiation of SSCs, and thereby bone repair. Mechanistically, we revealed that CCL1 enhanced expression level of basic leucine zipper ATF-like transcription factor (BATF) in CCR8+ Treg cells, which bound to Grn promoter and increased Grn translational output and then PGRN secretion. Together, our work provides a new perspective in osteoimmunology and highlights possible ways of manipulating Treg cell signaling to enhance bone repair and regeneration.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604943","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
Prospective observational study and mechanistic evidence showing lipolysis of circulating triglycerides worsens hypertriglyceridemic acute pancreatitis. 前瞻性观察研究和机理证据显示,循环中甘油三酯的脂肪分解会加重高甘油三酯急性胰腺炎。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-07 DOI: 10.1172/JCI184785
Prasad Rajalingamgari, Biswajit Khatua, Megan J Summers, Sergiy Kostenko, Yu-Hui H Chang, Mohamed Elmallahy, Arti Anand, Anoop Narayana Pillai, Mahmoud Morsy, Shubham Trivedi, Bryce McFayden, Sarah Jahangir, Christine Lh Snozek, Vijay P Singh

Background: While most hypertriglyceridemia is asymptomatic, hypertriglyceridemia-associated acute pancreatitis (HTG-AP) can be more severe than other AP etiologies. The reasons underlying this are unclear. We thus studied whether lipolytic generation of non-esterified fatty acids (NEFA) from circulating triglycerides (TGs) could worsen clinical outcomes.

Methods: Admission serum TGs, NEFA compositions and concentrations were analyzed prospectively in 269 patients with AP. These and demographics, clinical outcomes were compared between HTGAP (TGs >500mg/dL; American Heart Association 2018 guidelines) and other AP etiologies. Serum NEFAs were correlated with the serum triglyceride fatty acids (TGFAs) alone, and with the product of TGFA x serum lipase (NEFA-TGFA x lipase). Studies in mice, rats were done to understand the role of HTG lipolysis in organ failure and to interpret the NEFA-TGFA correlations.

Results: HTG-AP patients had higher serum NEFAs and TGs and more severe AP (19% vs. 7% p<0.03) than other etiologies. Correlations of long-chain unsaturated NEFA with corresponding TGFAs increased with TG concentrations up to 500mg/dL and declined thereafter. However, NEFA-TGFA x lipase correlations got stronger with TGs >500mg/dL. AP, and intravenous lipase infusion in rodents caused lipolysis of circulating TGs to NEFA. This led to multi-system organ failure, which was prevented by pancreatic triglyceride lipase deletion, or lipase inhibition.

Conclusions: HTG-AP is made severe by the NEFAs generated form intravascular lipolysis of circulating TGs. Strategies that prevent TG lipolysis may be effective in improving clinical outcomes of HTG-AP.

Trial registration: Not applicable.

Funding: This project was supported by Grant numbers RO1DK092460, R01DK119646 from the NIDDK, PR191945 under W81XWH-20-1-0400 from the DOD (VPS), and R01AA031257 from the NIAAA (VPS).

背景:虽然大多数高甘油三酯血症无症状,但高甘油三酯血症相关急性胰腺炎(HTG-AP)可能比其他急性胰腺炎病因更严重。其原因尚不清楚。因此,我们研究了从循环甘油三酯(TGs)中生成非酯化脂肪酸(NEFA)的脂肪分解作用是否会恶化临床预后:方法:我们对 269 例 AP 患者的入院血清 TGs、NEFA 成分和浓度进行了前瞻性分析。这些数据与人口统计学、临床预后在 HTGAP(TG>500mg/dL;美国心脏协会 2018 年指南)和其他 AP 病因之间进行了比较。血清 NEFA 单独与血清甘油三酯脂肪酸(TGFA)相关,也与 TGFA x 血清脂肪酶的乘积(NEFA-TGFA x 脂肪酶)相关。对小鼠和大鼠进行了研究,以了解 HTG 脂肪分解在器官衰竭中的作用,并解释 NEFA-TGFA 的相关性:结果:HTG-AP 患者的血清 NEFA 和 TG 值更高,AP 更严重(19% 对 7% p500mg/dL)。在啮齿类动物中,AP 和静脉注射脂肪酶会导致循环中的 TG 脂肪分解为 NEFA。这导致了多系统器官衰竭,而胰腺甘油三酯脂肪酶缺失或脂肪酶抑制剂可防止这种衰竭:结论:循环中甘油三酯在血管内脂解产生的 NEFA 使 HTG-AP 变得严重。防止 TG 脂肪分解的策略可能有效改善 HTG-AP 的临床预后:不适用:本项目得到了美国国立卫生研究院(NIDDK)的 RO1DK092460 和 R01DK119646 号拨款、美国国防部(DOD)W81XWH-20-1-0400 号 PR191945 号拨款(VPS)以及美国国立卫生研究院(NIAAA)R01AA031257 号拨款(VPS)的支持。
{"title":"Prospective observational study and mechanistic evidence showing lipolysis of circulating triglycerides worsens hypertriglyceridemic acute pancreatitis.","authors":"Prasad Rajalingamgari, Biswajit Khatua, Megan J Summers, Sergiy Kostenko, Yu-Hui H Chang, Mohamed Elmallahy, Arti Anand, Anoop Narayana Pillai, Mahmoud Morsy, Shubham Trivedi, Bryce McFayden, Sarah Jahangir, Christine Lh Snozek, Vijay P Singh","doi":"10.1172/JCI184785","DOIUrl":"https://doi.org/10.1172/JCI184785","url":null,"abstract":"<p><strong>Background: </strong>While most hypertriglyceridemia is asymptomatic, hypertriglyceridemia-associated acute pancreatitis (HTG-AP) can be more severe than other AP etiologies. The reasons underlying this are unclear. We thus studied whether lipolytic generation of non-esterified fatty acids (NEFA) from circulating triglycerides (TGs) could worsen clinical outcomes.</p><p><strong>Methods: </strong>Admission serum TGs, NEFA compositions and concentrations were analyzed prospectively in 269 patients with AP. These and demographics, clinical outcomes were compared between HTGAP (TGs >500mg/dL; American Heart Association 2018 guidelines) and other AP etiologies. Serum NEFAs were correlated with the serum triglyceride fatty acids (TGFAs) alone, and with the product of TGFA x serum lipase (NEFA-TGFA x lipase). Studies in mice, rats were done to understand the role of HTG lipolysis in organ failure and to interpret the NEFA-TGFA correlations.</p><p><strong>Results: </strong>HTG-AP patients had higher serum NEFAs and TGs and more severe AP (19% vs. 7% p<0.03) than other etiologies. Correlations of long-chain unsaturated NEFA with corresponding TGFAs increased with TG concentrations up to 500mg/dL and declined thereafter. However, NEFA-TGFA x lipase correlations got stronger with TGs >500mg/dL. AP, and intravenous lipase infusion in rodents caused lipolysis of circulating TGs to NEFA. This led to multi-system organ failure, which was prevented by pancreatic triglyceride lipase deletion, or lipase inhibition.</p><p><strong>Conclusions: </strong>HTG-AP is made severe by the NEFAs generated form intravascular lipolysis of circulating TGs. Strategies that prevent TG lipolysis may be effective in improving clinical outcomes of HTG-AP.</p><p><strong>Trial registration: </strong>Not applicable.</p><p><strong>Funding: </strong>This project was supported by Grant numbers RO1DK092460, R01DK119646 from the NIDDK, PR191945 under W81XWH-20-1-0400 from the DOD (VPS), and R01AA031257 from the NIAAA (VPS).</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604944","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
期刊
Journal of Clinical Investigation
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1