Journal of Clinical Investigation最新文献_第6页

Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-10 DOI: 10.1172/JCI184502

Subash Chand Verma, Emmanuelle Enée, Kanchanadevi Manasse, Feriel Rebhi, Axelle Penc, David Romeo-Guitart, Cuc Bui Thi, Matthias Titeux, Franck Oury, Simon Fillatreau, Roland Liblau, Julien Diana

{"title":"Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation.","authors":"Subash Chand Verma, Emmanuelle Enée, Kanchanadevi Manasse, Feriel Rebhi, Axelle Penc, David Romeo-Guitart, Cuc Bui Thi, Matthias Titeux, Franck Oury, Simon Fillatreau, Roland Liblau, Julien Diana","doi":"10.1172/JCI184502","DOIUrl":"https://doi.org/10.1172/JCI184502","url":null,"abstract":"Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS), the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We showed that, at early stage, CNS-recruited neutrophils produced neutrophil extracellular traps (NETs) rich in CRAMP that was required for EAE initiation. NET-associated CRAMP stimulated IL-6 production by dendritic cells via the cGAS/STING pathway, thereby promoting encephalitogenic Th17 response. However, at a later disease stage, neurons also expressed CRAMP that reduced EAE severity. Camp knockdown in neurons led to disease exacerbation, while local injection of CRAMP1-39 at the peak of EAE promoted disease remission. In vitro, CRAMP1-39 regulated the activation of microglia and astrocytes through the formyl peptide receptor (FPR)2. Finally, administration of butyrate, a gut microbiota-derived metabolite, stimulated the expression of neural CRAMP via the free fatty acids receptors (FFAR)2/3, and prevented EAE. This study shows that CRAMP produced by different cell types have opposing effects on neuroinflammation, offering therapeutic opportunities for MS and other neuroinflammatory disorders.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801033","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

C2230, a preferential use- and state-dependent CaV2.2 channel blocker, mitigates pain behaviors across multiple pain models.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-10 DOI: 10.1172/JCI177429

Cheng Tang, Kimberly Gomez, Yan Chen, Heather N Allen, Sara Hestehave, Erick J Rodríguez-Palma, Santiago Loya-Lopez, Aida Calderon-Rivera, Paz Duran, Tyler S Nelson, Siva Rama Raju Kanumuri, Bijal Shah, Nihar R Panigrahi, Samantha Perez-Miller, Morgan K Schackmuth, Shivani Ruparel, Amol Patwardhan, Theodore J Price, Paramjit S Arora, Ravindra K Sharma, Abhisheak Sharma, Jie Yu, Olga A Korczeniewska, Rajesh Khanna

{"title":"C2230, a preferential use- and state-dependent CaV2.2 channel blocker, mitigates pain behaviors across multiple pain models.","authors":"Cheng Tang, Kimberly Gomez, Yan Chen, Heather N Allen, Sara Hestehave, Erick J Rodríguez-Palma, Santiago Loya-Lopez, Aida Calderon-Rivera, Paz Duran, Tyler S Nelson, Siva Rama Raju Kanumuri, Bijal Shah, Nihar R Panigrahi, Samantha Perez-Miller, Morgan K Schackmuth, Shivani Ruparel, Amol Patwardhan, Theodore J Price, Paramjit S Arora, Ravindra K Sharma, Abhisheak Sharma, Jie Yu, Olga A Korczeniewska, Rajesh Khanna","doi":"10.1172/JCI177429","DOIUrl":"https://doi.org/10.1172/JCI177429","url":null,"abstract":"Antagonists (e.g., Ziconotide, Gabapentin) of the CaV2.2 (N-type) calcium channels are used clinically as analgesics for chronic pain. However, their use is limited by narrow therapeutic windows, difficult dosing routes (Ziconotide), misuse and overdoses (Gabapentin), as well as a litany of adverse effects. Expansion of novel pain therapeutics may emerge from mechanism-based interrogation of CaV2.2. Here we report the identification of C2230, an aryloxy-hydroxypropylamine, as a CaV2.2 blocker. C2230 trapped and stabilized inactivated CaV2.2 in a slow-recovering state and accelerated the open-state inactivation of the channel, conferring an advantageous use-dependent inhibition profile. C2230 inhibited CaV2.2 during high-frequency stimulation, while sparing other voltage-gated ion channels. C2230 inhibited CaV2.2 in dorsal root and trigeminal ganglia neurons from rats, marmosets, and humans in a G-protein-coupled receptor-independent manner. Further, C2230 reduced evoked excitatory postsynaptic currents and excitatory neurotransmitter release in the spinal cord, leading to relief of neuropathic, orofacial, and osteoarthritic pain-like behaviors via three different routes of administration. C2230 also decreased fiber photometry-based calcium responses in the parabrachial nucleus, mitigated aversive behavioral responses to mechanical stimuli after neuropathic injury, and preserved protective pain responses, all without affecting motor or cardiovascular function. Finally, site-directed mutation analysis demonstrated that C2230 binds differently than other known CaV2.2 blockers, making it a promising lead compound for analgesic development.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801031","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

Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-03 DOI: 10.1172/JCI183409

Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y Eugene Chen, Lin Chang

{"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":"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.","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}

引用次数: 0

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-02 DOI: 10.1172/JCI185569

Hong Wang, Maria Miranda, Eizo Marutani, Paul Lichtenegger, Gregory R Wojtkiewicz, Fumito Ichinose, Vamsi K Mootha

引用次数: 0

HO-1 impairs the efficacy of radiotherapy by redistributing cGAS and STING in tumors.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-02 DOI: 10.1172/JCI181044

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

{"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":"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.","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}

引用次数: 0

Taking the STING out of radiotherapy: STING checkpoints mediate radiation resistance.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-02 DOI: 10.1172/JCI186547

Michael C Brown, Justin T Low, Michelle L Bowie, David M Ashley

引用次数: 0

Sex, cells, and metabolism: Androgens temper Th17-mediated immunity.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-02 DOI: 10.1172/JCI186520

Nikita L Mani, Samuel E Weinberg

引用次数: 0

Palmitoylation acts as a checkpoint for MAVS aggregation to promote antiviral innate immune responses.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-02 DOI: 10.1172/JCI177924

Liqiu Wang, Mengqiu Li, Guangyu Lian, Shuai Yang, Jing Cai, Zhe Cai, Yaoxing Wu, Jun Cui

{"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":"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.","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}

引用次数: 0

Reduced thymic IL-4 impairs negative T cell selection in nonobese diabetic mice.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-02 DOI: 10.1172/JCI163417

Alexis N Cattin-Roy, Kimberly G Laffey, Luan B Le, Adam G Schrum, Habib Zaghouani

{"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":"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.","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}

引用次数: 0

Dysregulated Treg repair responses lead to chronic rejection after heart transplantation.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-02 DOI: 10.1172/JCI173593

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

{"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":"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.","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}

引用次数: 0