JCI insight最新文献_第3页

Flotillin-2 dampens T cell antigen-sensitivity and functionality. Flotillin-2 可抑制 T 细胞的抗原敏感性和功能。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-05 DOI: 10.1172/jci.insight.182328

Sookjin Moon, Fei Zhao, Mohammad N Uddin, Charles J Tucker, Peer Wf Karmaus, Michael B Fessler

{"title":"Flotillin-2 dampens T cell antigen-sensitivity and functionality.","authors":"Sookjin Moon, Fei Zhao, Mohammad N Uddin, Charles J Tucker, Peer Wf Karmaus, Michael B Fessler","doi":"10.1172/jci.insight.182328","DOIUrl":"https://doi.org/10.1172/jci.insight.182328","url":null,"abstract":"T cell receptor (TCR) engagement triggers T cell responses, yet how TCR-mediated activation is regulated at the plasma membrane remains unclear. Here, we report that deleting the membrane scaffolding protein Flotillin-2 (Flot2) increases T cell antigen-sensitivity, resulting in enhanced TCR signaling and effector function to weak TCR stimulation. T cell-specific Flot2-deficient mice exhibited reduced tumor growth and enhanced immunity to infection. Flot2-null CD4+ T cells exhibited increased T helper 1 polarization, proliferation, Nur77 induction, and phosphorylation of ZAP70 and ERK1/2 upon weak TCR stimulation, indicating a sensitized TCR-triggering threshold. Single cell-RNA sequencing suggested that Flot2-null CD4+ T cells follow a similar route of activation as wild-type CD4+ T cells but exhibit higher occupancy of a discrete activation state under weak TCR stimulation. Given prior reports that TCR clustering influences sensitivity of T cells to stimuli, we evaluated TCR distribution with super-resolution microscopy. Flot2 ablation increased the number of surface TCR nanoclusters on naïve CD4+ T cells. Collectively, we posit that Flot2 modulates T cell functionality to weak TCR stimulation, at least in part, by regulating surface TCR clustering. Our findings have implications for improving T cell reactivity in diseases with poor antigenicity, such as cancer and chronic infections.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583258","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

LMAN1 serves as a cargo receptor for thrombopoietin. LMAN1 是血小板生成素的货物受体。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-05 DOI: 10.1172/jci.insight.175704

Lesley A Everett, Zesen Lin, Ann Friedman, Vi T Tang, Greggory Myers, Ginette Balbin-Cuesta, Richard King, Guojing Zhu, Beth McGee, Rami Khoriaty

{"title":"LMAN1 serves as a cargo receptor for thrombopoietin.","authors":"Lesley A Everett, Zesen Lin, Ann Friedman, Vi T Tang, Greggory Myers, Ginette Balbin-Cuesta, Richard King, Guojing Zhu, Beth McGee, Rami Khoriaty","doi":"10.1172/jci.insight.175704","DOIUrl":"https://doi.org/10.1172/jci.insight.175704","url":null,"abstract":"Thrombopoietin (TPO) is a plasma glycoprotein that binds its receptor on megakaryocytes (MK) and MK progenitors, resulting in enhanced platelet production. The mechanism by which TPO is secreted from hepatocytes remains poorly understood. LMAN1 and MCFD2 form a complex at the endoplasmic reticulum membrane, recruiting cargo proteins into COPII vesicles for secretion. In this study, we showed that LMAN1 deficient mice (with complete germline LMAN1 deficiency) exhibited mild thrombocytopenia, whereas the platelet count was entirely normal in mice with approximately 7% Lman1 expression. Surprisingly, mice deleted for Mcfd2 did not exhibit thrombocytopenia. Analysis of peripheral blood from LMAN1 deficient mice demonstrated normal platelet size and normal morphology of dense and alpha granules. LMAN1 deficient mice exhibited a trend toward reduced MK and MK progenitors in the bone marrow. We next showed that hepatocyte-specific but not hematopoietic Lman1 deletion results in thrombocytopenia, with plasma TPO level reduced in LMAN1 deficient mice, despite normal Tpo mRNA levels in LMAN1 deficient livers. TPO and LMAN1 interacted by co-immunoprecipitation in a heterologous cell line and TPO accumulated intracellularly in LMAN1 deleted cells. Altogether, these studies confirmed the hepatocyte as the cell of origin for TPO production in vivo and were consistent with LMAN1 as the endoplasmic reticulum cargo receptor that mediates the efficient secretion of TPO. To our knowledge, TPO is the first example of an LMAN1-dependent cargo that is independent of MCFD2.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583261","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

Reprogramming of epidermal keratinocytes by PITX1 transforms the cutaneous cellular landscape and promotes wound healing. PITX1 对表皮角质细胞的重编程改变了皮肤细胞的结构，促进了伤口愈合。

IF 6.3 1区医学

JCI insight Pub Date : 2024-10-31 DOI: 10.1172/jci.insight.182844

Andrew M Overmiller, Akihiko Uchiyama, Emma D Hope, Subhashree Nayak, Christopher G O'Neill, Kowser Hasneen, Yi-Wen Chen, Faiza Naz, Stefania Dell'Orso, Stephen R Brooks, Kan Jiang, Maria I Morasso

{"title":"Reprogramming of epidermal keratinocytes by PITX1 transforms the cutaneous cellular landscape and promotes wound healing.","authors":"Andrew M Overmiller, Akihiko Uchiyama, Emma D Hope, Subhashree Nayak, Christopher G O'Neill, Kowser Hasneen, Yi-Wen Chen, Faiza Naz, Stefania Dell'Orso, Stephen R Brooks, Kan Jiang, Maria I Morasso","doi":"10.1172/jci.insight.182844","DOIUrl":"10.1172/jci.insight.182844","url":null,"abstract":"Cutaneous wound healing is a slow process that often terminates with permanent scarring while oral wounds, in contrast, regenerate damage faster. Unique molecular networks in epidermal and oral epithelial keratinocytes contribute to the tissue-specific response to wounding, but key factors that establish those networks and how the keratinocytes interact with their cellular environment remain to be elucidated. The transcription factor PITX1 is highly expressed in the oral epithelium but is undetectable in cutaneous keratinocytes. To delineate if PITX1 contributes to oral keratinocyte identity, cell-cell interactions, and the improved wound healing capabilities, we ectopically expressed PITX1 in the epidermis of murine skin. Using comparative analysis of murine skin and oral (buccal) mucosa with scRNA-seq and spatial transcriptomics, we found that PITX1 expression enhances epidermal keratinocyte migration, proliferation, and alters differentiation to a quasi-oral keratinocyte state. PITX1+ keratinocytes reprogram intercellular communication between skin-resident cells to mirror buccal tissue while also stimulating the influx of neutrophils that establish a pro-inflammatory environment. Furthermore, PITX1+ skin heals significantly faster than control skin via increased keratinocyte activation and migration and a tunable inflammatory environment. These results illustrate that PITX1 programs oral keratinocyte identity and cellular interactions while also revealing critical downstream networks that promote wound closure.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557859","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

Dynamic transcriptome analysis of osteal macrophages identifies distinct subset with senescence features in experimental osteoporosis. 骨膜巨噬细胞的动态转录组分析确定了实验性骨质疏松症中具有衰老特征的独特亚群。

IF 6.3 1区医学

JCI insight Pub Date : 2024-10-31 DOI: 10.1172/jci.insight.182418

Yoshio Nishida, M Alaa Terkawi, Gen Matsumae, Shunichi Yokota, Taiki Tokuhiro, Yuki Ogawa, Hotaka Ishizu, Junki Shiota, Tsutomu Endo, Hend Alhasan, Taku Ebata, Keita Kitahara, Tomohiro Shimizu, Daisuke Takahashi, Masahiko Takahata, Ken Kadoya, Norimasa Iwasaki

{"title":"Dynamic transcriptome analysis of osteal macrophages identifies distinct subset with senescence features in experimental osteoporosis.","authors":"Yoshio Nishida, M Alaa Terkawi, Gen Matsumae, Shunichi Yokota, Taiki Tokuhiro, Yuki Ogawa, Hotaka Ishizu, Junki Shiota, Tsutomu Endo, Hend Alhasan, Taku Ebata, Keita Kitahara, Tomohiro Shimizu, Daisuke Takahashi, Masahiko Takahata, Ken Kadoya, Norimasa Iwasaki","doi":"10.1172/jci.insight.182418","DOIUrl":"10.1172/jci.insight.182418","url":null,"abstract":"Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence and apoptotic process. A scRNA-seq analysis revealed that osteal macrophages were heterogenously clustered into 6 subsets that expressed proliferative, inflammatory, anti-inflammatory and efferocytosis gene signatures. Importantly, postmenopausal mice exhibited a 20-fold increase in subset-3 that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopause altered the osteal macrophages subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment. Furthermore, adoptive macrophage transfer onto calvarial bone was performed and mice that received oxidative-stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in development of inflammaging in bone microenvironment. Consistently, depletion of senescent cells and oxidative-stressed macrophages subset alleviated the excessive bone loss in postmenopausal mice. Our data provided a new insight into the pathogenesis of osteoporosis and sheds light on a new therapeutic approach for the treatment/prevention of postmenopausal osteoporosis.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557858","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

ASCL1 regulates and cooperates with FOXA2 to drive terminal neuroendocrine phenotype in prostate cancer. ASCL1 调节并与 FOXA2 合作驱动前列腺癌的终末神经内分泌表型。

IF 6.3 1区医学

JCI insight Pub Date : 2024-10-29 DOI: 10.1172/jci.insight.185952

Shaghayegh Nouruzi, Takeshi Namekawa, Nakisa Tabrizian, Maxim Kobelev, Olena Sivak, Joshua M Scurll, Cassandra Jingjing Cui, Dwaipayan Ganguli, Amina Zoubeidi

{"title":"ASCL1 regulates and cooperates with FOXA2 to drive terminal neuroendocrine phenotype in prostate cancer.","authors":"Shaghayegh Nouruzi, Takeshi Namekawa, Nakisa Tabrizian, Maxim Kobelev, Olena Sivak, Joshua M Scurll, Cassandra Jingjing Cui, Dwaipayan Ganguli, Amina Zoubeidi","doi":"10.1172/jci.insight.185952","DOIUrl":"https://doi.org/10.1172/jci.insight.185952","url":null,"abstract":"Lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the lineage plasticity driving neuroendocrine differentiation. Here, we showed that ASCL1 was reprogrammed in ARPI-induced transition to the terminal NEPC and identified that the ASCL1 binding pattern tailored the expression of lineage-determinant transcription factor combinations that underlying discrete terminal NEPC identity. Notably, we identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC, which is highly expressed in ASCL1-driven NEPC. Mechanistically, FOXA2 and ASCL1 interacted and worked in concert to orchestrate terminal neuronal differentiation. We identified that Prospero-Related Homeobox 1 was a target of ASCL1 and FOXA2. Targeting prospero-related homeobox 1 abrogated neuroendocrine characteristics and led to a decrease in cell proliferation in vitro and tumor growth in vivo. Our findings provide insights into the molecular conduit underlying the interplay between different lineage-determinant transcription factors to support the neuroendocrine identity and nominate prospero-related homeobox 1 as a potential target in ASCL1 high NEPC.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545558","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

HIV-1 latency reversal agent boosting is not limited by opioid use. HIV-1 潜伏期逆转剂的增强作用不受使用阿片类药物的限制。

IF 6.3 1区医学

JCI insight Pub Date : 2024-10-29 DOI: 10.1172/jci.insight.185480

Tyler J Lilie, Jennifer Bouzy, Archana Asundi, Jessica Taylor, Samantha Roche, Alex Olson, Kendyll Coxen, Heather Corry, Hannah Jordan, Kiera Clayton, Nina Lin, Athe Tsibris

{"title":"HIV-1 latency reversal agent boosting is not limited by opioid use.","authors":"Tyler J Lilie, Jennifer Bouzy, Archana Asundi, Jessica Taylor, Samantha Roche, Alex Olson, Kendyll Coxen, Heather Corry, Hannah Jordan, Kiera Clayton, Nina Lin, Athe Tsibris","doi":"10.1172/jci.insight.185480","DOIUrl":"10.1172/jci.insight.185480","url":null,"abstract":"Opioid use may impact the HIV-1 reservoir and its reversal from latency. We studied forty-seven virally suppressed people with HIV (PWH) and observed that lower concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that did not reverse latency, synergistically increased the magnitude of HIV-1 re-activation ex vivo, regardless of opioid use. This LRA boosting, which combined a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, generated significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation, modulated surface activation-induced markers, and altered T cell production of TNFα, IL-2, and IFNγ. HIV-1 reservoirs in PWH contained unspliced and polyadenylated (polyA) virus mRNA, the ratios of which were greater in resting than total CD4+ T cells and correct to 1:1 with PMAi exposure. We characterized treated suppressed HIV-1 infection as a period of inefficient, not absent, virus transcription. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe mechanisms of an effective cellular HIV-1 latency reversal program.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545561","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

Comprehensive analysis of mesenchymal cells reveals a dysregulated TGF-β/Wnt/HOXB7 axis in patients with myelofibrosis. 对间充质细胞的全面分析表明，骨髓纤维化患者体内的 TGF-β/Wnt/HOXB7 轴失调。

IF 6.3 1区医学

JCI insight Pub Date : 2024-10-29 DOI: 10.1172/jci.insight.173665

Saravanan Ganesan, Sarah Awan-Toor, Fabien Guidez, Nabih Maslah, Rifkath Rahimy, Céline Aoun, Panhong Gou, Chloé Guiguen, Juliette Soret, Odonchimeg Ravdan, Valeria Bisio, Nicolas Dulphy, Camille Lobry, Marie-Hélène Schlageter, Michèle Souyri, Stéphane Giraudier, Jean-Jacques Kiladjian, Christine Chomienne, Bruno Cassinat

{"title":"Comprehensive analysis of mesenchymal cells reveals a dysregulated TGF-β/Wnt/HOXB7 axis in patients with myelofibrosis.","authors":"Saravanan Ganesan, Sarah Awan-Toor, Fabien Guidez, Nabih Maslah, Rifkath Rahimy, Céline Aoun, Panhong Gou, Chloé Guiguen, Juliette Soret, Odonchimeg Ravdan, Valeria Bisio, Nicolas Dulphy, Camille Lobry, Marie-Hélène Schlageter, Michèle Souyri, Stéphane Giraudier, Jean-Jacques Kiladjian, Christine Chomienne, Bruno Cassinat","doi":"10.1172/jci.insight.173665","DOIUrl":"https://doi.org/10.1172/jci.insight.173665","url":null,"abstract":"Despite the advances in the understanding and treatment of myeloproliferative neoplasm (MPN), the disease remains incurable with the risk of evolution to AML or myelofibrosis (MF). Unfortunately, the evolution of the disease to MF remains still poorly understood impeding preventive and therapeutic options. Recent studies in solid tumor microenvironment and organ fibrosis have shed instrumental insights on their respective pathogenesis and drug resistance, yet such precise data are lacking in MPN. In this study, through a patient-sample driven transcriptomic and epigenetic description of the MF microenvironment landscape and cell-based analyses, we identify HOXB7 overexpression and more precisely a novel TGFβ-Wnt-HOXB7 pathway as associated to a pro-fibrotic and pro-osteoblastic biased differentiation of mesenchymal stromal cells (MSCs). Using gene-based and chemical inhibition of this pathway we reverse the abnormal phenotype of MSCs from myelofibrosis patients, providing the MPN field with a potential novel target to prevent and manage evolution to MF.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545559","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

Aldosterone-induced salt appetite requires HSD2 neurons. 醛固酮诱导的盐食欲需要 HSD2 神经元。

IF 6.3 1区医学

JCI insight Pub Date : 2024-10-24 DOI: 10.1172/jci.insight.175087

Silvia Gasparini, Lila Peltekian, Miriam C McDonough, Chidera Ja Mitchell, Marco Hefti, Jon M Resch, Joel C Geerling

{"title":"Aldosterone-induced salt appetite requires HSD2 neurons.","authors":"Silvia Gasparini, Lila Peltekian, Miriam C McDonough, Chidera Ja Mitchell, Marco Hefti, Jon M Resch, Joel C Geerling","doi":"10.1172/jci.insight.175087","DOIUrl":"https://doi.org/10.1172/jci.insight.175087","url":null,"abstract":"Excessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption may worsen end-organ damage in patients with aldosteronism. Preventing this increase could improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we previously identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). In the present study, we identified HSD2 neurons in the human brain, then used a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirmed that dietary sodium deprivation increases aldosterone production, salt intake, and HSD2 neuron activity. Next, we showed that continuous chemogenetic stimulation of HSD2 neurons causes a large and specific increase in salt intake. Finally, we use dose-response studies and genetically targeted ablation of HSD2 neurons to show that these neurons are necessary for aldosterone-induced salt intake. Identifying HSD2 neurons in the human brain and establishing their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500735","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

The contribution of neutrophils to bacteriophage clearance and pharmacokinetics in vivo. 中性粒细胞对体内噬菌体清除和药代动力学的贡献

IF 6.3 1区医学

JCI insight Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.181309

Arne Echterhof, Tejas Dharmaraj, Arya Khosravi, Robert McBride, Lynn Miesel, Ju-Hsin Chia, Patrick M Blankenberg, Kun-Yuan Lin, Chien-Chang Shen, Yu-Ling Lee, Yu-Chuan Yeh, Wei Ting Liao, Francis G Blankenberg, Krystyna Dąbrowska, Derek F Amanatullah, Adam R Frymoyer, Paul L Bollyky

{"title":"The contribution of neutrophils to bacteriophage clearance and pharmacokinetics in vivo.","authors":"Arne Echterhof, Tejas Dharmaraj, Arya Khosravi, Robert McBride, Lynn Miesel, Ju-Hsin Chia, Patrick M Blankenberg, Kun-Yuan Lin, Chien-Chang Shen, Yu-Ling Lee, Yu-Chuan Yeh, Wei Ting Liao, Francis G Blankenberg, Krystyna Dąbrowska, Derek F Amanatullah, Adam R Frymoyer, Paul L Bollyky","doi":"10.1172/jci.insight.181309","DOIUrl":"10.1172/jci.insight.181309","url":null,"abstract":"With the increasing prevalence of antimicrobial-resistant bacterial infections, there is interest in using bacteriophages (phages) to treat such infections. However, the factors that govern bacteriophage pharmacokinetics in vivo remain poorly understood. Here, we have examined the contribution of neutrophils, the most abundant phagocytes in the body, to the pharmacokinetics of i.v. administered bacteriophage in uninfected mice. A single dose of LPS-5, a bacteriophage recently used in human clinical trials to treat drug-resistant Pseudomonas aeruginosa, was administered i.v. to both immunocompetent BALB/c and neutropenic CD1 mice. Phage concentrations were assessed in peripheral blood and spleen at 0.25, 1, 2, 4, 8, 12, and 24 hours after administration by plaque assay and qPCR. We observed that the phage clearance was only minimally affected by neutropenia. Indeed, the half-lives of phages in blood in BALB/c and CD1 mice were 3.45 and 3.66 hours, respectively. These data suggest that neutrophil-mediated phagocytosis is not a major determinant of phage clearance. Conversely, we observed a substantial discrepancy in circulating phage levels over time when measured by qPCR versus plaque assay, suggesting that significant inactivation of circulating phages occurs over time. These data indicate that alternative factors, but not neutrophils, inactivate i.v. administered phages.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465885","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

Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation. 迁移性 CD103+ 树突状细胞的后天免疫刺激表型会促进角膜移植后的异体免疫。

IF 6.3 1区医学

JCI insight Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.182469

Tomás Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I Shoushtari, Reza Dana

{"title":"Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation.","authors":"Tomás Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I Shoushtari, Reza Dana","doi":"10.1172/jci.insight.182469","DOIUrl":"10.1172/jci.insight.182469","url":null,"abstract":"After transplantation, Th1-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ DCs (DC2) and CD103+ DCs (DC1). This interaction necessitates further investigation in the context of transplant immunity. We used well-established preclinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+ DC1 demonstrate a tolerogenic phenotype that modulates the immunogenic capacity of CD11b+ DC2 primarily mediated by IL-10, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGF-β1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+ Th1 cells induced migratory CD103+ DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers, including αvβ8 integrin and IL-10, and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex vivo induced tolerogenic CD103+ DC1 (iDC1) effectively inhibited Th1 polarization and preserved the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+ DC1 in modulating host alloimmune responses.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140146","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