Journal of Clinical Investigation最新文献

{"title":"Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure.","authors":"Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y Eugene Chen, Lin Chang","doi":"10.1172/JCI183409","DOIUrl":"https://doi.org/10.1172/JCI183409","url":null,"abstract":"<p><p>Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease (CVD). Thus, gaining insights into the molecular mechanisms of BP circadian variation is essential for comprehending BP regulation. Human genetic analyses suggest that PR domain-containing protein 16 (PRDM16), a transcription factor highly expressed in vascular smooth muscle cells (VSMC), is significantly associated with BP-related traits. However, the roles of PRDM16 in BP regulation are largely unknown. Here, we demonstrate that BP in VSMC-specific Prdm16 knockout (Prdm16SMKO) mice was significantly lower than that in control mice during the active period, resulting in aberrant BP circadian variation. Mesenteric artery rings from Prdm16SMKO mice showed reduced response to phenylephrine. Mechanistically, we identified adrenergic receptor alpha 1d (Adra1d) as a transcriptional target of PRDM16. Notably, PRDM16 exhibits a remarkable circadian expression pattern and regulates the expression of clock genes, particularly Npas2, which is crucial for BP circadian variation regulation. Consequently, PRDM16 deficiency in VSMC causes disrupted BP circadian variation through reduced response to adrenergic signaling and clock gene regulation. Our findings offer substantial insights into the intricate molecular pathways that govern circadian fluctuations in BP.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769416","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}

{"title":"Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α.","authors":"Hong Wang, Maria Miranda, Eizo Marutani, Paul Lichtenegger, Gregory R Wojtkiewicz, Fumito Ichinose, Vamsi K Mootha","doi":"10.1172/JCI185569","DOIUrl":"https://doi.org/10.1172/JCI185569","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 23","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769433","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}

{"title":"HO-1 impairs the efficacy of radiotherapy by redistributing cGAS and STING in tumors.","authors":"Chuqing Zhang, Zhenji Deng, Jiawei Wu, Cong Ding, Zhe Li, Zhimin Xu, Weipeng Chen, Kaibin Yang, Hanmiao Wei, Tingxiang He, Liufen Long, Jun Ma, Cheng Xu, Xiaoyu Liang","doi":"10.1172/JCI181044","DOIUrl":"https://doi.org/10.1172/JCI181044","url":null,"abstract":"<p><p>Type I IFNs (IFN-Is) induced by radiotherapy (RT) are critical for its efficacy, while the mechanism by which tumor cells inhibit IFN-I production remains largely unsolved. By an unbiased CRISPR screen, we identified hemeoxygenase 1 (HO-1) as an RT-related regulator of IFN-I production. Mechanistically, the ER-anchored, full-length HO-1 disrupted stimulator of IFN genes (STING) polymerization and subsequent coat protein complex II-mediated (COPII-mediated) ER-Golgi transportation, leading to hampered activation of downstream signaling. This process was exacerbated by the upregulation of HO-1 expression under RT. Importantly, RT also induced HO-1 cleavage. Cleaved HO-1 underwent nuclear translocation, interacted with cyclic GMP-AMP synthase (cGAS), and inhibited its nuclear export upon irradiation, leading to suppressed 2'3'-cyclic GMP-AMP (cGAMP) production. Furthermore, we revealed that HO-1 inhibitors could enhance local and distant tumor control of RT in vivo. Clinically, higher HO-1 expression was associated with a poorer prognosis and earlier tumor relapse after RT in multiple types of patient tumors. Collectively, through comprehensive inhibition of the cGAS/STING pathway, HO-1 strongly inhibited RT-induced IFN-I production, and targeting HO-1 was shown to be a promising RT-sensitizing therapeutic strategy.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 23","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769399","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}

{"title":"Taking the STING out of radiotherapy: STING checkpoints mediate radiation resistance.","authors":"Michael C Brown, Justin T Low, Michelle L Bowie, David M Ashley","doi":"10.1172/JCI186547","DOIUrl":"10.1172/JCI186547","url":null,"abstract":"<p><p>The cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway is a critical driver of type I interferon (IFN-I) and antitumor CD8+ T cell responses after radiotherapy (RT). In this issue of the JCI, two reports describe mechanisms that restrained STING signaling and abrogated antitumor immunity after RT. Wen, Wang, and colleagues discovered that IFN-I mediated the induction of YTHDF1, an RNA N6-methyladenosine-binding protein, in DCs after RT promoted cathepsin-mediated STING degradation. Zhang, Deng, Wu, and colleagues discovered that hemeoxygenase 1 (HO-1) was induced and proteolytically cleaved after RT to suppress cGAS cytoplasmic export as well as STING oligomerization at the ER. Blocking the STING-suppressive functions of YTHDF1 and HO-1, respectively, improved antitumor T cell immunity and tumor control after RT. Together, these studies support the development of clinical avenues to sustain STING signaling during RT, a standard treatment for approximately 50% of malignancies.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 23","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769430","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}

{"title":"Sex, cells, and metabolism: Androgens temper Th17-mediated immunity.","authors":"Nikita L Mani, Samuel E Weinberg","doi":"10.1172/JCI186520","DOIUrl":"https://doi.org/10.1172/JCI186520","url":null,"abstract":"<p><p>Sex-based differences in autoimmune disease susceptibility have long been recognized, prompting investigations into how sex hormones influence immunity. Recent advances suggest that hormones may shape immune responses by altering cellular metabolism. In this issue of the JCI, Chowdhury et al. authenticates this model, showing that androgen receptor signaling modulates T helper 17 (Th17) cell metabolism, specifically glutaminolysis, reducing airway inflammation in males. This work provides insight into sex-specific regulation of immunity, highlighting the interplay between hormones, metabolism, and immune function. The findings raise intriguing questions about how hormonal fluctuations affect immunity and how sex-specific metabolic pathways might be leveraged for targeted therapies in autoimmune diseases.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 23","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769424","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}

{"title":"Palmitoylation acts as a checkpoint for MAVS aggregation to promote antiviral innate immune responses.","authors":"Liqiu Wang, Mengqiu Li, Guangyu Lian, Shuai Yang, Jing Cai, Zhe Cai, Yaoxing Wu, Jun Cui","doi":"10.1172/JCI177924","DOIUrl":"https://doi.org/10.1172/JCI177924","url":null,"abstract":"<p><p>Upon RNA virus infection, the signaling adaptor MAVS forms functional prion-like aggregates on the mitochondrial outer membrane, which serve as a central hub that links virus recognition to downstream antiviral innate immune responses. Multiple mechanisms regulating MAVS activation have been revealed; however, the checkpoint governing MAVS aggregation remains elusive. Here, we demonstrated that the palmitoylation of MAVS at cysteine 79 (C79), which is catalyzed mainly by the palmitoyl S-acyltransferase ZDHHC12, was essential for MAVS aggregation and antiviral innate immunity upon viral infection in macrophages. Notably, the systemic lupus erythematosus-associated mutation MAVS C79F was associated with defective palmitoylation, resulting in low type I interferon (IFN) production. Accordingly, Zdhhc12 deficiency apparently impaired RNA virus-induced type I IFN responses, and Zdhhc12-deficient mice were highly susceptible to lethal viral infection. These findings reveal a previously unknown mechanism by which the palmitoylation of MAVS is a checkpoint for its aggregation during viral infection to ensure timely activation of antiviral defense.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 23","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769401","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}

{"title":"Reduced thymic IL-4 impairs negative T cell selection in nonobese diabetic mice.","authors":"Alexis N Cattin-Roy, Kimberly G Laffey, Luan B Le, Adam G Schrum, Habib Zaghouani","doi":"10.1172/JCI163417","DOIUrl":"https://doi.org/10.1172/JCI163417","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c+CD8α+ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 23","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769419","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}

{"title":"Dysregulated Treg repair responses lead to chronic rejection after heart transplantation.","authors":"Jordan Jp Warunek, Lu Fan, Xue Zhang, Sihua Wang, Steven M Sanders, Tengfang Li, Lisa R Mathews, Gaelen K Dwyer, Michelle A Wood-Trageser, Stephanie Traczek, Andrew Lesniak, Kassandra Baron, Hailey Spencer, Johnny Bou Saba, Emmanuel León Colón, Tracy Tabib, Robert Lafyatis, Mark A Ross, Anthony J Demetris, Simon C Watkins, Steven A Webber, Khodor I Abou-Daya, Hēth R Turnquist","doi":"10.1172/JCI173593","DOIUrl":"10.1172/JCI173593","url":null,"abstract":"<p><p>Chronic rejection (CR) after organ transplantation is alloimmune injury manifested by graft vascular remodeling and fibrosis that is resistant to immunosuppression. Single-cell RNA-Seq analysis of MHC class II-mismatched (MHCII-mismatched) heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating macrophages and Tregs. Using IL-33-deficient donor mice, we show that graft fibroblast-derived IL-33 potently induced amphiregulin (Areg) expression by recipient Tregs. The assessment of clinical samples also confirmed increased expression of Areg by intragraft Tregs also during rejection. Areg is an EGF secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessment of recipient mice with Treg-specific deletion of Areg surprisingly uncovered that Treg secretion of Areg contributed to CR. Specifically, heart transplants from recipients with Areg-deficient Tregs showed less fibrosis, vasculopathy, and vessel-associated fibrotic niches populated by recipient T cells. Mechanistically, we show that Treg-secreted Areg functioned to increase fibroblast proliferation. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Tregs contributed to the progression of CR.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 23","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769396","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}

{"title":"Supportive care or exhausted neglect: the role of microglia at the end stage of prion disease.","authors":"Victoria A Lawson","doi":"10.1172/JCI186940","DOIUrl":"https://doi.org/10.1172/JCI186940","url":null,"abstract":"<p><p>The transmissible nature of prion diseases enables reproduction of neurodegeneration in small animal models that faithfully follows the disease process observed in the natural disease of animals and humans. This allows the temporal development of disease to be investigated and correlated with pathology in a complex brain environment. In this issue of the JCI, Makarava et al. describe a shift in microglia morphology from an active phagocytic phenotype to a passive association with neuronal cell bodies. Whether this morphological change reflects a supportive action of microglia in response to neuronal impairment or exhaustion of PrPSc-laden microglia remains to be determined. However, if microglial populations effectively contain PrPSc propagation early in the infection process, as the current study suggests, identifying ways to maintain or enhance the function of this cell population could be the key to prolonging patient survival.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 23","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769427","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}

{"title":"Assessing advances in three decades of clinical antiretroviral therapy on the HIV-1 reservoir.","authors":"Irene González-Navarro, Víctor Urrea, Cristina Gálvez, Maria Del Carmen Garcia-Guerrero, Sara Morón-López, Maria C Puertas, Eulàlia Grau, Beatriz Mothe, Lucía Bailón, Cristina Miranda, Felipe García, Lorna Leal, Linos Vandekerckhove, Vincent C Marconi, Rafick P Sekaly, Bonaventura Clotet, Javier Martinez-Picado, Maria Salgado","doi":"10.1172/JCI183952","DOIUrl":"10.1172/JCI183952","url":null,"abstract":"<p><p>BACKGROUNDAntiretroviral therapy (ART) has improved the clinical management of HIV-1 infection. However, little is known about how the latest ART recommendations affect the heterogeneity of the HIV-1 reservoir size.METHODSWe used a complete statistical approach to outline parameters underlying the diversity in HIV-1 reservoir size in a cohort of 892 people with HIV-1 (PWH) on suppressive ART for more than 3 years. Total HIV-1-DNA levels were measured in PBMCs using digital droplet PCR (ddPCR).RESULTSWe classified 179 (20%) participants as being low viral reservoir treated (LoViReT) (<50 HIV-1-DNA copies/106 PBMCs). Twenty variables were collected to explore their association with the LoViReT phenotype using machine learning approaches. LoViReT status was closely associated with higher nadir CD4, lower zenith pre-ART viral load, lower CD4 recovery, shorter time from diagnosis to undetectable viral load, and initiation of treatment with an integrase inhibitor-containing (InSTI-containing) regimen. Initiation of ART with any InSTI was also linked with a shorter time to undetectable viremia. Locally estimated scatterplot smoothing (LOESS) regression revealed a progressive reduction in the size of the HIV-1 reservoir in individuals who started ART after 2007. Similarly, a higher nadir CD4 and a shorter time to undetectable viremia were observed when treatment was initiated after that year.CONCLUSIONOur findings demonstrate that the progressive implementation of earlier, universal treatment at diagnosis and the use of InSTIs affected the size of the HIV-1 reservoir. Our work shows that effective management of infection is the first step toward reducing the reservoir and brings us closer to achieving a cure.FUNDINGNIH; Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID), NIH; Merck Sharp & Dohme.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750465","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}