The Journal of Clinical Investigation最新文献_第4页

Targeting hepatic cholesterol sensing to tackle metabolic dysfunction-associated steatohepatitis. 靶向肝脏胆固醇传感解决代谢功能障碍相关的脂肪性肝炎。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci206628

Mengwei Zang,Yu Li

引用次数: 0

Gut microbe-derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice. 肠道微生物来源的短链脂肪酸调节小鼠甲病毒关节炎和巨噬细胞活化。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci202262

Fang R Zhao,Maksim Kleverov,Emma S Winkler,Russell B Williams,Hana Janova,Lindsay Droit,Leran Wang,Ting-Ting Li,Leah Heath,Ana Jung,Matthias Mack,Megan T Baldridge,Thaddeus S Stappenbeck,Larissa B Thackray,Chyi-Song Hsieh,Scott A Handley,Chun-Jun Guo,Michael A Fischbach,Maxim N Artyomov,Michael S Diamond

{"title":"Gut microbe-derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice.","authors":"Fang R Zhao,Maksim Kleverov,Emma S Winkler,Russell B Williams,Hana Janova,Lindsay Droit,Leran Wang,Ting-Ting Li,Leah Heath,Ana Jung,Matthias Mack,Megan T Baldridge,Thaddeus S Stappenbeck,Larissa B Thackray,Chyi-Song Hsieh,Scott A Handley,Chun-Jun Guo,Michael A Fischbach,Maxim N Artyomov,Michael S Diamond","doi":"10.1172/jci202262","DOIUrl":"https://doi.org/10.1172/jci202262","url":null,"abstract":"Oral antibiotics can predispose to joint inflammation, but this phenomenon remains poorly understood. Here, we leverage mouse models of alphavirus-induced arthritis to investigate the roles of gut commensals, metabolites, and host immune mechanisms in promoting musculoskeletal inflammation. Mice treated with a short course of oral antibiotics exhibited worsened arthritis after chikungunya (CHIKV) or Mayaro virus infections. This phenotype was associated with loss of short-chain fatty acids (SCFAs), greater intestinal permeability, and activation of gut-associated immune cells and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4+ T cells, and proinflammatory cytokines. Administration of exogenous SCFAs or colonization of mice with bacterial species that generate SCFAs mitigated CHIKV-induced joint inflammation. scRNA-seq revealed that gut-derived SCFAs ameliorate the inflammatory phenotype of synovial CD4+ T cells, infiltrating monocytes, and resident osteoclast-like cells. Thus, antibiotic-triggered gut dysbiosis exacerbates alphavirus arthritis by shaping the inflammatory profile of both infiltrating and resident immune cells in joint tissues.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"294 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441157","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}

引用次数: 0

Sterol biosynthesis, brain development, and disease. 固醇生物合成，大脑发育和疾病。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci208000

Eric S Peeples,Zeljka Korade,Karoly Mirnics

{"title":"Sterol biosynthesis, brain development, and disease.","authors":"Eric S Peeples,Zeljka Korade,Karoly Mirnics","doi":"10.1172/jci208000","DOIUrl":"https://doi.org/10.1172/jci208000","url":null,"abstract":"Cholesterol biosynthesis is indispensable for CNS development and function. The developing brain relies almost entirely on intrinsic sterol synthesis to support membrane biogenesis, axonal outgrowth, synaptogenesis, and myelination. Pathogenic variants in sterol biosynthetic enzymes, including DHCR7 and DHCR24, result in complex neurodevelopmental disorders such as Smith-Lemli-Opitz syndrome and desmosterolosis. In addition to cholesterol-lowering drugs (statins), some other pharmacological agents such as antipsychotics, antidepressants, and beta blockers can also inhibit cholesterol biosynthesis due to off-target effects. This inhibition produces dual pathophysiological effects: cholesterol depletion and accumulation of its precursor, 7-dehydrocholesterol, an exceptionally oxidizable molecule that spontaneously generates toxic oxysterols. Given the intense demand for cholesterol synthesis in the developing brain, prenatal exposure to sterol biosynthesis-inhibiting medications may have far-reaching effects. In this Review, we describe convergent biochemical, genetic, and epidemiologic data that implicate developmental sterol dysregulation as a modifiable risk factor for neurodevelopmental pathology and underscore the urgent need for routine sterol pathway safety assessment in drug development and prenatal pharmacotherapy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441033","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}

引用次数: 0

Antigen-specific type 1 regulatory T cell responses shape immunity and disease tolerance in human malaria. 抗原特异性1型调节性T细胞反应影响人类疟疾的免疫和疾病耐受性。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci208046

Leonie Brockmann

引用次数: 0

Histone lysine methyltransferases KMT2C and KMT2D join the all-star tumor suppressor team in gastrointestinal cancer. 组蛋白赖氨酸甲基转移酶KMT2C和KMT2D加入了胃肠道肿瘤抑制的全明星团队。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci208392

Nicole M Peña Ruiz,Martin E Fernandez-Zapico

引用次数: 0

Migration-dependent extrafollicular programming of pre-plasmablast age-associated B cells drives lupus pathogenesis. 浆质前年龄相关B细胞的迁移依赖滤泡外编程驱动狼疮发病机制。

The Journal of Clinical Investigation Pub Date : 2026-07-14 DOI: 10.1172/jci204095

Taiichiro Shirai,Kentaro Kuzuya,Mizuki Kishi,Shinya Ichikawa,Shuhei Sakakibara,Akiko Nakai,Sarah Leach,Yu-Chen Liu,Daisuke Motooka,Daisuke Okuzaki,Masashi Narazaki,Atsushi Kumanogoh,Tomohiro Kurosaki,Jun Saegusa,Kazuhiro Suzuki

{"title":"Migration-dependent extrafollicular programming of pre-plasmablast age-associated B cells drives lupus pathogenesis.","authors":"Taiichiro Shirai,Kentaro Kuzuya,Mizuki Kishi,Shinya Ichikawa,Shuhei Sakakibara,Akiko Nakai,Sarah Leach,Yu-Chen Liu,Daisuke Motooka,Daisuke Okuzaki,Masashi Narazaki,Atsushi Kumanogoh,Tomohiro Kurosaki,Jun Saegusa,Kazuhiro Suzuki","doi":"10.1172/jci204095","DOIUrl":"https://doi.org/10.1172/jci204095","url":null,"abstract":"Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production. Extrafollicular (EF) B cell responses contribute to SLE pathogenesis, with age-associated B cells (ABCs) giving rise to autoantibody-secreting plasmablasts (PBs). However, the migratory cues governing this EF trajectory remain unclear. Here, we identify a distinct ABC state with PB precursor characteristics (pre-PB ABCs) and reveal a migration-dependent program underlying their generation. Single-cell analysis of SLE patients and model mice showed that pre-PB ABCs were enriched in autoreactive clones and poised for PB differentiation. Their frequency correlated with autoantibody titers and disease activity, underscoring their pathogenic relevance. We further demonstrated that the oxysterol receptor EBI2 directed ABCs to EF niches within splenic bridging channels, promoting pre-PB ABC formation and autoreactive PB output. This process depended on the COMMD3/8 complex, a positive regulator of chemoattractant receptor signaling. Beyond EBI2-mediated ABC migration to EF niches, the COMMD3/8 complex was also required for trafficking of autoantibody-secreting cells to the bone marrow and infiltration of ABCs into the kidney. Accordingly, COMMD3/8 complex inhibition ameliorated disease in murine SLE models. These findings define a migration-dependent mechanism driving the EF differentiation of ABCs into autoreactive PBs and shaping the tissue distribution of pathogenic B cells, highlighting this program as a potential therapeutic target in SLE.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441168","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}

引用次数: 0

A favorable follicular helper CD4 T cell programming characterizes neutralization activity in chronic HIV infection. 一个有利的滤泡辅助CD4 T细胞编程特征中和活性在慢性HIV感染。

The Journal of Clinical Investigation Pub Date : 2026-07-14 DOI: 10.1172/jci192575

Eirini Moysi,Ashish A Sharma,Sijy O'Dell,Spiros Georgakis,Perla Mariana Del Rio Estrada,Ghneim Khader,Alonso Arana,Fernanda Torres-Ruiz,Mauricio González Navarro,Yara Andrea Luna Villalobos,Santiago Avila Rios,Gustavo Reyes-Teran,Margaret H Beddall,Sung Hee Ko,Frida Belinky,Michail Orfanakis,Laurence de Leval,Ana B Enriquez,Clarisa M Buckner,Susan Moir,Helen Lindsay,Raphael Gottardo,Nicole Doria-Rose,Eli A Boritz,John R Mascola,Rafick-Pierre Sekaly,Richard A Koup,Constantinos Petrovas

{"title":"A favorable follicular helper CD4 T cell programming characterizes neutralization activity in chronic HIV infection.","authors":"Eirini Moysi,Ashish A Sharma,Sijy O'Dell,Spiros Georgakis,Perla Mariana Del Rio Estrada,Ghneim Khader,Alonso Arana,Fernanda Torres-Ruiz,Mauricio González Navarro,Yara Andrea Luna Villalobos,Santiago Avila Rios,Gustavo Reyes-Teran,Margaret H Beddall,Sung Hee Ko,Frida Belinky,Michail Orfanakis,Laurence de Leval,Ana B Enriquez,Clarisa M Buckner,Susan Moir,Helen Lindsay,Raphael Gottardo,Nicole Doria-Rose,Eli A Boritz,John R Mascola,Rafick-Pierre Sekaly,Richard A Koup,Constantinos Petrovas","doi":"10.1172/jci192575","DOIUrl":"https://doi.org/10.1172/jci192575","url":null,"abstract":"A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these antibodies are poorly understood. Here, we explored LN-associated histological, immunological, and virological determinants of bNAb generation in a cohort of anti-retroviral therapy (ART)-naïve PLWH. We found that participants who produce bNAbs, termed neutralizers, have a better-preserved LN-associated B cell follicle architecture compared with PLWH who do not. The former was associated with a substantially higher in situ prevalence of Bcl-6hi follicular helper CD4 T cells (TFH), expressing a molecular program that favors their differentiation and stemness, and substantially reduced IL-10 follicular suppressor CD4 T cells. Furthermore, our data reveal possible molecular targets mediating TFH- B cell interactions in neutralizers. Together, we identify germinal center cellular and molecular signatures that could contribute to the development of bNAbs in PLWH.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441169","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}

引用次数: 0

Sensory neuron BRAF mediates opioid-induced hyperalgesia and tolerance via presynaptic NMDA receptor hyperactivity. 感觉神经元BRAF通过突触前NMDA受体亢进介导阿片诱导的痛觉过敏和耐受性。

The Journal of Clinical Investigation Pub Date : 2026-07-14 DOI: 10.1172/jci201808

Daozhong Jin,Hong Chen,Yuying Huang,Shao-Rui Chen,Hui-Lin Pan

{"title":"Sensory neuron BRAF mediates opioid-induced hyperalgesia and tolerance via presynaptic NMDA receptor hyperactivity.","authors":"Daozhong Jin,Hong Chen,Yuying Huang,Shao-Rui Chen,Hui-Lin Pan","doi":"10.1172/jci201808","DOIUrl":"https://doi.org/10.1172/jci201808","url":null,"abstract":"Opioids are essential analgesics for managing severe pain but can paradoxically increase pain sensitivity (hyperalgesia) and diminish analgesic efficacy (tolerance). Hyperactivity of NMDA-type glutamate receptors (NMDARs) at primary afferent terminals in the spinal cord contributes to both phenomena; however, the underlying signaling mechanisms remain unclear. Here, we report that morphine administration in rats promoted the translocation of monomeric BRAF, an oncogenic kinase, from the dorsal root ganglion (DRG) to spinal cord synaptosomes, leading to increased MEK-ERK phosphorylation at nociceptor central terminals. BRAF physically interacted with NMDARs in both rat and human spinal cords. Inhibition of BRAF activity with vemurafenib reversed morphine-induced NMDAR phosphorylation and synaptic localization of α2δ-1-bound NMDARs. Vemurafenib also abolished morphine-induced presynaptic NMDAR hyperactivity in spinal dorsal horn neurons. Correspondingly, conditional Braf knockout in DRG neurons normalized morphine-enhanced NMDAR phosphorylation, synaptic trafficking of α2δ-1-bound NMDARs, and NMDAR hyperactivity in the spinal cord. Furthermore, pharmacological inhibition of BRAF or MEK, or Braf deletion in DRG neurons, enhanced morphine analgesia while mitigated morphine-induced hyperalgesia and tolerance. These findings identify BRAF overactivity at nociceptor central terminals as a key mediator of opioid-induced NMDAR hyperactivity. Clinically approved BRAF inhibitors could be repurposed to enhance opioid analgesia while minimizing adverse effects.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"250 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441185","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}

引用次数: 0

Disruption of methionine metabolism drives erythroid cell fate reprogramming by remodeling the H3K4me3 landscape. 蛋氨酸代谢的破坏通过重塑H3K4me3景观驱动红细胞命运重编程。

The Journal of Clinical Investigation Pub Date : 2026-07-14 DOI: 10.1172/jci203565

Lei Sun,Hengchao Zhang,Mengjia Li,Quande Lin,Xiuyun Wu,Ying Cheng,Shihui Wang,Yan Hou,Yaomei Wang,Yue Sheng,Jing Liu,Xiuli An,Ting Wang,Lixiang Chen

{"title":"Disruption of methionine metabolism drives erythroid cell fate reprogramming by remodeling the H3K4me3 landscape.","authors":"Lei Sun,Hengchao Zhang,Mengjia Li,Quande Lin,Xiuyun Wu,Ying Cheng,Shihui Wang,Yan Hou,Yaomei Wang,Yue Sheng,Jing Liu,Xiuli An,Ting Wang,Lixiang Chen","doi":"10.1172/jci203565","DOIUrl":"https://doi.org/10.1172/jci203565","url":null,"abstract":"Methionine cycle plays critical roles in cell fate determination by shaping epigenetic landscape, yet its function in human erythropoiesis remains undefined. Here, we show that disruption of methionine metabolism by compromising key enzyme adenosylhomocysteinase (AHCY) reshapes H3K4me3 landscape, causing erythroid cell fate reprogramming. AHCY deficiency severely impaired erythroid differentiation and expansion, leading to the generation of non-erythroid lineage hematopoietic cells, including stem/progenitor cells and immune cells, as evidenced by single-cell RNA sequencing, Pseudo temporal analysis delineated a precise dedifferentiation trajectory, revealing erythroblasts transitioning back to MEPs and HSCs. Moreover, human hematopoietic system could be reconstituted in the immunodeficient NCG-X mice by transplanting AHCY deficient erythroblasts. Mechanistically, AHCY deficiency reduced global H3K4me3 levels and altered its genomic distribution, resulting in the upregulated expression of non-erythroid transcription factors and downregulated expression of erythrocyte lineage-specific transcription factors. Integrated single-cell analyses identified transitional states with diminished AHCY in the erythroblasts of acute myeloid leukemia (AML) patient. Further flow cytometry confirmed the reduced H3K4me3 level in patient derived erythroid cells. Erythroblasts isolated from AML patients with reduced H3K4me3 exhibited dedifferentiation potential into progenitor-like states. Our findings reveal a metabolic-epigenetic axis governing cell fate reprogramming in human erythropoiesis and provide insights into leukemia associated anemia.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441186","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}

引用次数: 0

Distinct parafascicular neuronal ensembles mediate the sensory and affective dimensions of trigeminal neuralgia. 不同的束旁神经元群介导三叉神经痛的感觉和情感维度。

The Journal of Clinical Investigation Pub Date : 2026-07-14 DOI: 10.1172/jci206862

Yitian Lu,Yangyang Yi,Jiao Liu,Hao Zhi,Qing Chang,Zihao Huang,Yumeng Chen,Han L Tan,Yiheng Tu,Yun Wang,Cheng Cen

{"title":"Distinct parafascicular neuronal ensembles mediate the sensory and affective dimensions of trigeminal neuralgia.","authors":"Yitian Lu,Yangyang Yi,Jiao Liu,Hao Zhi,Qing Chang,Zihao Huang,Yumeng Chen,Han L Tan,Yiheng Tu,Yun Wang,Cheng Cen","doi":"10.1172/jci206862","DOIUrl":"https://doi.org/10.1172/jci206862","url":null,"abstract":"Trigeminal neuralgia (TN) is a severe orofacial pain disorder accompanied by anxiety, yet its central mechanisms remain elusive. Analysis of human fMRI data identified the parafascicular nucleus (PF) as a candidate region. Using a TN mouse model, we uncovered two spatially and functionally distinct PF neuronal ensembles that separately encoded sensory and affective dimensions of pain. One population received inhibitory input from GABAergic neurons in the oral spinal trigeminal nucleus (Sp5O) and mediated nociception. The second population, driven by a glutamatergic Sp5O-lateral parabrachial nucleus (lPBN)-PF pathway, encoded pain-related anxiety. The engagement of the anxiety-encoding ensemble lagged behind that of the pain-encoding ensemble, with a shorter delay in females. Single-nucleus RNA sequencing identified Col25a1 and Syn2 as markers of the anxiety-encoding ensemble. Notably, this population, localized in the medial PF, formed a reciprocal lPBN-mPF-lPBN excitatory-feedback loop that sustained affective pain. These findings positioned PF as a key node linking pain and emotion in TN.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"97 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441188","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}

引用次数: 0