Pub Date : 2025-01-15DOI: 10.1126/scitranslmed.adj1445
Ewa A. Ziółkowska, Matthew J. Jansen, Letitia L. Williams, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takahashi, Steven Q. Le, Hemanth R. Nelvagal, Jaiprakash Sharma, Marco Sardiello, Brian J. DeBosch, Patricia I. Dickson, Jessica B. Anderson, Sophie E. Sax, Christina M. Wright, Rebecca P. Bradley, Ineka T. Whiteman, Takako Makita, John R. Grider, Mark S. Sands, Robert O. Heuckeroth, Jonathan D. Cooper
Children with neurodegenerative disease often have debilitating gastrointestinal symptoms. We hypothesized that this may be due at least in part to underappreciated degeneration of neurons in the enteric nervous system (ENS), the master regulator of bowel function. To test this hypothesis, we evaluated mouse models of neuronal ceroid lipofuscinosis type 1 and 2 (CLN1 and CLN2 disease, respectively), neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 and tripeptidyl peptidase-1, respectively. Both mouse lines displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally in these mice, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Similar pathology was evident in colon autopsy material from a child with CLN1 disease. Neonatal administration of adeno-associated virus–mediated gene therapy prevented bowel transit defects, ameliorated loss of enteric neurons, and extended survival in mice. Treatment after weaning was less effective than treating neonatally but still extended the lifespan of CLN1 disease mice. These data provide proof-of-principle evidence of ENS degeneration in two lysosomal storage diseases and suggest that gene therapy can ameliorate ENS disease, also improving survival.
{"title":"Gene therapy ameliorates bowel dysmotility and enteric neuron degeneration and extends survival in lysosomal storage disorder mouse models","authors":"Ewa A. Ziółkowska, Matthew J. Jansen, Letitia L. Williams, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takahashi, Steven Q. Le, Hemanth R. Nelvagal, Jaiprakash Sharma, Marco Sardiello, Brian J. DeBosch, Patricia I. Dickson, Jessica B. Anderson, Sophie E. Sax, Christina M. Wright, Rebecca P. Bradley, Ineka T. Whiteman, Takako Makita, John R. Grider, Mark S. Sands, Robert O. Heuckeroth, Jonathan D. Cooper","doi":"10.1126/scitranslmed.adj1445","DOIUrl":"10.1126/scitranslmed.adj1445","url":null,"abstract":"<div >Children with neurodegenerative disease often have debilitating gastrointestinal symptoms. We hypothesized that this may be due at least in part to underappreciated degeneration of neurons in the enteric nervous system (ENS), the master regulator of bowel function. To test this hypothesis, we evaluated mouse models of neuronal ceroid lipofuscinosis type 1 and 2 (CLN1 and CLN2 disease, respectively), neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 and tripeptidyl peptidase-1, respectively. Both mouse lines displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally in these mice, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Similar pathology was evident in colon autopsy material from a child with CLN1 disease. Neonatal administration of adeno-associated virus–mediated gene therapy prevented bowel transit defects, ameliorated loss of enteric neurons, and extended survival in mice. Treatment after weaning was less effective than treating neonatally but still extended the lifespan of CLN1 disease mice. These data provide proof-of-principle evidence of ENS degeneration in two lysosomal storage diseases and suggest that gene therapy can ameliorate ENS disease, also improving survival.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 781","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986488","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}
Pub Date : 2025-01-15DOI: 10.1126/scitranslmed.adr6459
Baijie Xu, Katherine Lawler, Steven C. Wyler, Li Li, Swati, Julia M. Keogh, Xiameng Chen, Rong Wan, Amanda G. Almeida, Susan Kirsch, Kathleen G. Mountjoy, Joel K. Elmquist, I. Sadaf Farooqi, Chen Liu
Disruption of hypothalamic melanocortin 4 receptors (MC4Rs) causes obesity in mice and humans. Here, we investigated the transcriptional regulation of MC4R in the hypothalamus. In mice, we show that the homeodomain transcription factor Orthopedia (OTP) is enriched in MC4R neurons in the paraventricular nucleus (PVN) of the hypothalamus and directly regulates Mc4r transcription. Deletion of Otp in PVN neurons during development or adulthood reduced Mc4r expression, causing increased food intake and obesity. In humans, four of the five carriers of rare predicted functional OTP variants in UK Biobank had obesity. To explore a causal role for human OTP variants, we generated mice with a loss-of-function OTP mutation identified in a child with severe obesity. Heterozygous knock-in mice exhibited hyperphagia and obesity, reversed by treatment with an MC4R agonist. Our findings demonstrate that OTP regulates mammalian energy homeostasis and enable the diagnosis and treatment of individuals with obesity due to OTP deficiency.
{"title":"Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis","authors":"Baijie Xu, Katherine Lawler, Steven C. Wyler, Li Li, Swati, Julia M. Keogh, Xiameng Chen, Rong Wan, Amanda G. Almeida, Susan Kirsch, Kathleen G. Mountjoy, Joel K. Elmquist, I. Sadaf Farooqi, Chen Liu","doi":"10.1126/scitranslmed.adr6459","DOIUrl":"10.1126/scitranslmed.adr6459","url":null,"abstract":"<div >Disruption of hypothalamic melanocortin 4 receptors (MC4Rs) causes obesity in mice and humans. Here, we investigated the transcriptional regulation of <i>MC4R</i> in the hypothalamus. In mice, we show that the homeodomain transcription factor Orthopedia (OTP) is enriched in MC4R neurons in the paraventricular nucleus (PVN) of the hypothalamus and directly regulates <i>Mc4r</i> transcription. Deletion of <i>Otp</i> in PVN neurons during development or adulthood reduced <i>Mc4r</i> expression, causing increased food intake and obesity. In humans, four of the five carriers of rare predicted functional <i>OTP</i> variants in UK Biobank had obesity. To explore a causal role for human <i>OTP</i> variants, we generated mice with a loss-of-function <i>OTP</i> mutation identified in a child with severe obesity. Heterozygous knock-in mice exhibited hyperphagia and obesity, reversed by treatment with an MC4R agonist. Our findings demonstrate that OTP regulates mammalian energy homeostasis and enable the diagnosis and treatment of individuals with obesity due to <i>OTP</i> deficiency.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 781","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011098","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}
Pub Date : 2025-01-15DOI: 10.1126/scitranslmed.adn8699
Li-Li Bao, Yu-Qiang Yu, Miguel González-Acera, Jay V. Patankar, Andreas Giessl, Gregor Sturm, Anja A. Kühl, Raja Atreya, Lena Erkert, Reyes Gámez-Belmonte, Susanne M. Krug, Benjamin Schmid, Philipp Tripal, Mircea T. Chiriac, Kai Hildner, Britta Siegmund, Stefan Wirtz, Michael Stürzl, Mariam Mohamed Abdou, Zlatko Trajanoski, TRR241 IBDome Consortium, Markus F. Neurath, Antonio Zorzano, Christoph Becker
Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation. We found reduced expression of mitochondrial fusion–related genes, such as the dynamin-related guanosine triphosphatase (GTPase) optic atrophy 1 (OPA1), and fragmented mitochondrial networks in crypt IECs of patients with IBD. Mice with Opa1 deficiency in the gut epithelium (Opa1i∆IEC) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in Opa1i∆IEC mice was driven by microbial translocation and associated with epithelial progenitor cell death and gut barrier dysfunction. Opa1-deficient epithelial cells and human organoids exposed to a pharmacological OPA1 inhibitor showed disruption of the mitochondrial network with mitochondrial fragmentation and changes in mitochondrial size, ultrastructure, and function, resembling changes observed in patient samples. Pharmacological inhibition of the GTPase dynamin-1–like protein in organoids derived from Opa1i∆IEC mice partially reverted this phenotype. Together, our data demonstrate a role for epithelial OPA1 in regulating intestinal immune homeostasis and epithelial barrier function. Our data provide a mechanistic explanation for the observed mitochondrial dysfunction in IBD and identify mitochondrial fusion as a potential therapeutic target in this disease.
{"title":"Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease","authors":"Li-Li Bao, Yu-Qiang Yu, Miguel González-Acera, Jay V. Patankar, Andreas Giessl, Gregor Sturm, Anja A. Kühl, Raja Atreya, Lena Erkert, Reyes Gámez-Belmonte, Susanne M. Krug, Benjamin Schmid, Philipp Tripal, Mircea T. Chiriac, Kai Hildner, Britta Siegmund, Stefan Wirtz, Michael Stürzl, Mariam Mohamed Abdou, Zlatko Trajanoski, TRR241 IBDome Consortium, Markus F. Neurath, Antonio Zorzano, Christoph Becker","doi":"10.1126/scitranslmed.adn8699","DOIUrl":"10.1126/scitranslmed.adn8699","url":null,"abstract":"<div >Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation. We found reduced expression of mitochondrial fusion–related genes, such as the dynamin-related guanosine triphosphatase (GTPase) optic atrophy 1 (<i>OPA1</i>), and fragmented mitochondrial networks in crypt IECs of patients with IBD. Mice with <i>Opa1</i> deficiency in the gut epithelium (<i>Opa1<sup>i∆IEC</sup></i>) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in <i>Opa1<sup>i∆IEC</sup></i> mice was driven by microbial translocation and associated with epithelial progenitor cell death and gut barrier dysfunction. <i>Opa1</i>-deficient epithelial cells and human organoids exposed to a pharmacological OPA1 inhibitor showed disruption of the mitochondrial network with mitochondrial fragmentation and changes in mitochondrial size, ultrastructure, and function, resembling changes observed in patient samples. Pharmacological inhibition of the GTPase dynamin-1–like protein in organoids derived from <i>Opa1<sup>i∆IEC</sup></i> mice partially reverted this phenotype. Together, our data demonstrate a role for epithelial OPA1 in regulating intestinal immune homeostasis and epithelial barrier function. Our data provide a mechanistic explanation for the observed mitochondrial dysfunction in IBD and identify mitochondrial fusion as a potential therapeutic target in this disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 781","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011102","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}
Macrophages play a central role in antitumor immunity, making them an attractive target for gene therapy strategies. However, macrophages are difficult to transfect because of nucleic acid sensors that can trigger the degradation of foreign plasmid DNA. Here, we developed a macrophage-specific editing (MAGE) system by which compact plasmid DNA encoding a CasRx editor can be delivered to macrophages by a poly(β-amino ester) (PBAE) carrier to bypass the DNA sensor and enable RNA editing in vitro and in vivo. We identified a four-arm branched PBAE with 1-(2-aminoethyl)-4-methylpiperazine end-capping (PBAE29) that enables highly efficient macrophage transfection. PBAE29-mediated transfection of cultured macrophages stimulated less inflammatory cytokine production and inflammasome activation compared with traditional lipofectamine or electroporation-mediated plasmid delivery. Transfection efficiency was further improved by delivering CasRx by minicircle plasmid. The MAGE system incorporated a layer of carboxylated-mannan coating to target macrophage mannose receptors and a macrophage-specific promoter for enhanced selectivity. The delivery of CasRx with guide RNA targeting the transcripts for sialic acid–binding immunoglobulin similar to lectin 10 and signal regulatory protein alpha expression resulted in effective protein knockdown, improving macrophage phagocytosis. The MAGE system also showed efficacy in targeting macrophages in vivo, stimulating antitumor immune responses and reducing tumor volume in murine tumor models, including patient-derived pancreatic adenocarcinoma xenografts in humanized mice. In sum, the MAGE system presents a promising platform for in vivo macrophage-specific delivery of RNA editing tools that can be applied as a cancer therapy.
{"title":"Macrophage-specific in vivo RNA editing promotes phagocytosis and antitumor immunity in mice","authors":"Yuxuan Chen, Xiaohong Chen, Yao Zhang, Meng Wang, Minqi Yang, Ruiji Wang, Xiaojie Yan, Shiyi Shao, Huhu Xin, Qida Hu, Wei Wei, Yuan Ping","doi":"10.1126/scitranslmed.adl5800","DOIUrl":"10.1126/scitranslmed.adl5800","url":null,"abstract":"<div >Macrophages play a central role in antitumor immunity, making them an attractive target for gene therapy strategies. However, macrophages are difficult to transfect because of nucleic acid sensors that can trigger the degradation of foreign plasmid DNA. Here, we developed a macrophage-specific editing (MAGE) system by which compact plasmid DNA encoding a CasRx editor can be delivered to macrophages by a poly(β-amino ester) (PBAE) carrier to bypass the DNA sensor and enable RNA editing in vitro and in vivo. We identified a four-arm branched PBAE with 1-(2-aminoethyl)-4-methylpiperazine end-capping (PBAE29) that enables highly efficient macrophage transfection. PBAE29-mediated transfection of cultured macrophages stimulated less inflammatory cytokine production and inflammasome activation compared with traditional lipofectamine or electroporation-mediated plasmid delivery. Transfection efficiency was further improved by delivering CasRx by minicircle plasmid. The MAGE system incorporated a layer of carboxylated-mannan coating to target macrophage mannose receptors and a macrophage-specific promoter for enhanced selectivity. The delivery of CasRx with guide RNA targeting the transcripts for sialic acid–binding immunoglobulin similar to lectin 10 and signal regulatory protein alpha expression resulted in effective protein knockdown, improving macrophage phagocytosis. The MAGE system also showed efficacy in targeting macrophages in vivo, stimulating antitumor immune responses and reducing tumor volume in murine tumor models, including patient-derived pancreatic adenocarcinoma xenografts in humanized mice. In sum, the MAGE system presents a promising platform for in vivo macrophage-specific delivery of RNA editing tools that can be applied as a cancer therapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 781","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986490","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}
Pub Date : 2025-01-15DOI: 10.1126/scitranslmed.ado6649
Xiaotian Ju, Nahal Emami Fard, Anurag Bhalla, Anna Dvorkin-Gheva, Maria Xiao, Katherine Radford, Kayla Zhang, Reina Ditta, John Paul Oliveria, Guillaume Paré, Manali Mukherjee, Parameswaran Nair, Roma Sehmi
In prednisone-dependent severe asthma, uncontrolled sputum eosinophilia is associated with increased numbers of group 2 innate lymphoid cells (ILC2s). These cells represent a relatively steroid-insensitive source of interleukin-5 (IL-5) and IL-13 and are considered critical drivers of asthma pathology. The abundance of ILC subgroups in severe asthma with neutrophilic or mixed granulocytic (both eosinophilic and neutrophilic) airway inflammation, prone to recurrent infective exacerbations, remains unclear. Here, we found by flow cytometry that sputum ILC3s are increased in severe asthma with intense airway neutrophilia, whereas equivalently raised sputum ILC2s and ILC3s were found in severe asthma with mixed granulocytic inflammation. Unbiased clustering analyses identified an “intermediate-ILC2” population displaying markers of both ILC2s (prostaglandin D2 receptor 2; CRTH2, IL-5, and IL-13) and ILC3s (c-kit and IL-17A) that were most abundant in severe asthma with mixed granulocytic airway inflammation. Intermediate ILC2s correlated with airway neutrophilia and were associated with increased amounts of IL-1β and IL-18 in sputum supernatants. Coculture of sort-purified canonical ILC2s with IL-1β and IL-18 in vitro up-regulated c-kit and IL-17A as well as gene expression profiles related to both type 2 and type 17 inflammatory pathways. Together, we have identified an intermediate-ILC2 phenotype in the airways of individuals with severe mixed granulocytic asthma, representing a candidate therapeutic target for controlling neutrophilic airway inflammation.
{"title":"A population of c-kit+ IL-17A+ ILC2s in sputum from individuals with severe asthma supports ILC2 to ILC3 trans-differentiation","authors":"Xiaotian Ju, Nahal Emami Fard, Anurag Bhalla, Anna Dvorkin-Gheva, Maria Xiao, Katherine Radford, Kayla Zhang, Reina Ditta, John Paul Oliveria, Guillaume Paré, Manali Mukherjee, Parameswaran Nair, Roma Sehmi","doi":"10.1126/scitranslmed.ado6649","DOIUrl":"10.1126/scitranslmed.ado6649","url":null,"abstract":"<div >In prednisone-dependent severe asthma, uncontrolled sputum eosinophilia is associated with increased numbers of group 2 innate lymphoid cells (ILC2s). These cells represent a relatively steroid-insensitive source of interleukin-5 (IL-5) and IL-13 and are considered critical drivers of asthma pathology. The abundance of ILC subgroups in severe asthma with neutrophilic or mixed granulocytic (both eosinophilic and neutrophilic) airway inflammation, prone to recurrent infective exacerbations, remains unclear. Here, we found by flow cytometry that sputum ILC3s are increased in severe asthma with intense airway neutrophilia, whereas equivalently raised sputum ILC2s and ILC3s were found in severe asthma with mixed granulocytic inflammation. Unbiased clustering analyses identified an “intermediate-ILC2” population displaying markers of both ILC2s (prostaglandin D<sub>2</sub> receptor 2; CRTH2, IL-5, and IL-13) and ILC3s (c-kit and IL-17A) that were most abundant in severe asthma with mixed granulocytic airway inflammation. Intermediate ILC2s correlated with airway neutrophilia and were associated with increased amounts of IL-1β and IL-18 in sputum supernatants. Coculture of sort-purified canonical ILC2s with IL-1β and IL-18 in vitro up-regulated c-kit and IL-17A as well as gene expression profiles related to both type 2 and type 17 inflammatory pathways. Together, we have identified an intermediate-ILC2 phenotype in the airways of individuals with severe mixed granulocytic asthma, representing a candidate therapeutic target for controlling neutrophilic airway inflammation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 781","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986489","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}
Pub Date : 2025-01-15DOI: 10.1126/scitranslmed.adk3690
Wesley Brandao, Nimansha Jain, Zhuoran Yin, Kilian L. Kleemann, Madison Carpenter, Xin Bao, Javier R. Serrano, Eric Tycksen, Ana Durao, Jen-Li Barry, Caroline Baufeld, Dilansu Guneykaya, Xiaoming Zhang, Alexandra Litvinchuk, Hong Jiang, Neta Rosenzweig, Kristen M. Pitts, Michael Aronchik, Taha Yahya, Tian Cao, Marcelo Kenzo Takahashi, Rajesh Krishnan, Hayk Davtyan, Jason D. Ulrich, Mathew Blurton-Jones, Ilya Ilin, Howard L. Weiner, David M. Holtzman, Oleg Butovsky
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre–neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.
{"title":"Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy","authors":"Wesley Brandao, Nimansha Jain, Zhuoran Yin, Kilian L. Kleemann, Madison Carpenter, Xin Bao, Javier R. Serrano, Eric Tycksen, Ana Durao, Jen-Li Barry, Caroline Baufeld, Dilansu Guneykaya, Xiaoming Zhang, Alexandra Litvinchuk, Hong Jiang, Neta Rosenzweig, Kristen M. Pitts, Michael Aronchik, Taha Yahya, Tian Cao, Marcelo Kenzo Takahashi, Rajesh Krishnan, Hayk Davtyan, Jason D. Ulrich, Mathew Blurton-Jones, Ilya Ilin, Howard L. Weiner, David M. Holtzman, Oleg Butovsky","doi":"10.1126/scitranslmed.adk3690","DOIUrl":"10.1126/scitranslmed.adk3690","url":null,"abstract":"<div >Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre–neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 781","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986487","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}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adr2218
Olivia M. Swanson, Qianyi E. Zhang, Elizabeth Van Itallie, Ming Tian, Alecia R. Brown, Caitlin Harris, Anyway Brenda Kapingidza, Brianna Rhodes, Lena M. Smith, Sravani Venkatayogi, Kenneth Cronin, McKenzie Frazier, Rob Parks, Maggie Bar, Chuancang Jiang, Joshua S. Martin Beem, Hwei-Ling Cheng, Jillian Davis, Kelly McGovern, Amanda Newman, Robert J. Edwards, Derek Cain, S. Munir Alam, Kevin Wiehe, Kevin O. Saunders, Priyamvada Acharya, Fred Alt, Barton F. Haynes, Mihai L. Azoitei
Elicitation of HIV broadly neutralizing antibodies (bnAbs) by vaccination first requires the activation of diverse precursors, followed by successive boosts that guide these responses to enhanced breadth through the acquisition of somatic mutations. Because HIV bnAbs contain mutations in their B cell receptors (BCRs) that are rarely generated during conventional B cell maturation, HIV vaccine immunogens must robustly engage and expand B cells with BCRs that contain these improbable mutations. Here, we engineered an immunogen that activates diverse precursors of an HIV V3-glycan bnAb and promotes their acquisition of a functionally critical improbable mutation. This immunogen was validated biochemically, structurally, and in three different humanized immunoglobulin mouse models that were designed to test HIV immunogens. These results provide a blueprint for rationally designing priming immunogens that explicitly target the elicitation of antibodies with functional yet improbable mutations.
{"title":"An engineered immunogen activates diverse HIV broadly neutralizing antibody precursors and promotes acquisition of improbable mutations","authors":"Olivia M. Swanson, Qianyi E. Zhang, Elizabeth Van Itallie, Ming Tian, Alecia R. Brown, Caitlin Harris, Anyway Brenda Kapingidza, Brianna Rhodes, Lena M. Smith, Sravani Venkatayogi, Kenneth Cronin, McKenzie Frazier, Rob Parks, Maggie Bar, Chuancang Jiang, Joshua S. Martin Beem, Hwei-Ling Cheng, Jillian Davis, Kelly McGovern, Amanda Newman, Robert J. Edwards, Derek Cain, S. Munir Alam, Kevin Wiehe, Kevin O. Saunders, Priyamvada Acharya, Fred Alt, Barton F. Haynes, Mihai L. Azoitei","doi":"10.1126/scitranslmed.adr2218","DOIUrl":"10.1126/scitranslmed.adr2218","url":null,"abstract":"<div >Elicitation of HIV broadly neutralizing antibodies (bnAbs) by vaccination first requires the activation of diverse precursors, followed by successive boosts that guide these responses to enhanced breadth through the acquisition of somatic mutations. Because HIV bnAbs contain mutations in their B cell receptors (BCRs) that are rarely generated during conventional B cell maturation, HIV vaccine immunogens must robustly engage and expand B cells with BCRs that contain these improbable mutations. Here, we engineered an immunogen that activates diverse precursors of an HIV V3-glycan bnAb and promotes their acquisition of a functionally critical improbable mutation. This immunogen was validated biochemically, structurally, and in three different humanized immunoglobulin mouse models that were designed to test HIV immunogens. These results provide a blueprint for rationally designing priming immunogens that explicitly target the elicitation of antibodies with functional yet improbable mutations.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935873","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}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adp9607
Simone Romeni, Elena Losanno, Daniele Emedoli, Luigi Albano, Filippo Agnesi, Carlo Mandelli, Lina Raffaella Barzaghi, Edoardo Pompeo, Cinzia Mura, Federica Alemanno, Andrea Tettamanti, Paola Castellazzi, Chiara Ciucci, Veronica Fossati, Laura Toni, Heike Caravati, Andrea Bandini, Ubaldo Del Carro, Federica Agosta, Massimo Filippi, Sandro Iannaccone, Pietro Mortini, Silvestro Micera
Spinal cord injury (SCI) causes severe motor and sensory deficits, and there are currently no approved treatments for recovery. Nearly 70% of patients with SCI experience pathological muscle cocontraction and spasticity, accompanied by clinical signs such as patellar hyperreflexia and ankle clonus. The integration of epidural electrical stimulation (EES) of the spinal cord with rehabilitation has substantial potential to improve recovery of motor functions; however, abnormal muscle cocontraction and spasticity may limit the benefit of these interventions and hinder the effectiveness of EES in promoting functional movements. High-frequency excitation block introduced in peripheral nerve stimulation could reduce abnormal activity and lead to more physiological activation patterns. Here, we evaluated the application of high-frequency EES (HF-EES) in alleviating undesired muscular cocontraction and spasticity in two patients with motor incomplete SCI implanted with a commercial 32-channel EES paddle commonly used for pain therapy. To design custom HF-EES protocols, we first mapped the muscles targeted by different EES configurations. Our results showed that HF-EES substantially reduced patellar reflex in one participant and eliminated both patellar reflex and ankle clonus in the other participant. By combining HF-EES and low-frequency EES (LF-EES) to enhance functional movements with intensive rehabilitation, we observed notable improvements in lower limb kinematics, muscle strength, and clinical lower limb motor assessments over the trial period. This study suggests that HF-EES could be an important supplementary tool in SCI treatment, emphasizing the importance of personalized rehabilitation approaches and advanced tools to optimize EES treatments and offering hope for individuals with SCI-related motor deficits.
{"title":"High-frequency epidural electrical stimulation reduces spasticity and facilitates walking recovery in patients with spinal cord injury","authors":"Simone Romeni, Elena Losanno, Daniele Emedoli, Luigi Albano, Filippo Agnesi, Carlo Mandelli, Lina Raffaella Barzaghi, Edoardo Pompeo, Cinzia Mura, Federica Alemanno, Andrea Tettamanti, Paola Castellazzi, Chiara Ciucci, Veronica Fossati, Laura Toni, Heike Caravati, Andrea Bandini, Ubaldo Del Carro, Federica Agosta, Massimo Filippi, Sandro Iannaccone, Pietro Mortini, Silvestro Micera","doi":"10.1126/scitranslmed.adp9607","DOIUrl":"10.1126/scitranslmed.adp9607","url":null,"abstract":"<div >Spinal cord injury (SCI) causes severe motor and sensory deficits, and there are currently no approved treatments for recovery. Nearly 70% of patients with SCI experience pathological muscle cocontraction and spasticity, accompanied by clinical signs such as patellar hyperreflexia and ankle clonus. The integration of epidural electrical stimulation (EES) of the spinal cord with rehabilitation has substantial potential to improve recovery of motor functions; however, abnormal muscle cocontraction and spasticity may limit the benefit of these interventions and hinder the effectiveness of EES in promoting functional movements. High-frequency excitation block introduced in peripheral nerve stimulation could reduce abnormal activity and lead to more physiological activation patterns. Here, we evaluated the application of high-frequency EES (HF-EES) in alleviating undesired muscular cocontraction and spasticity in two patients with motor incomplete SCI implanted with a commercial 32-channel EES paddle commonly used for pain therapy. To design custom HF-EES protocols, we first mapped the muscles targeted by different EES configurations. Our results showed that HF-EES substantially reduced patellar reflex in one participant and eliminated both patellar reflex and ankle clonus in the other participant. By combining HF-EES and low-frequency EES (LF-EES) to enhance functional movements with intensive rehabilitation, we observed notable improvements in lower limb kinematics, muscle strength, and clinical lower limb motor assessments over the trial period. This study suggests that HF-EES could be an important supplementary tool in SCI treatment, emphasizing the importance of personalized rehabilitation approaches and advanced tools to optimize EES treatments and offering hope for individuals with SCI-related motor deficits.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935876","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}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adk8623
A. Scott McCall, Sergey Gutor, Hari Tanjore, Ankita Burman, Taylor Sherrill, Micah Chapman, Carla L. Calvi, David Han, Jane Camarata, Raphael P. Hunt, David Nichols, Nicholas E. Banovich, William E. Lawson, Jason J. Gokey, Jonathan A. Kropski, Timothy S. Blackwell
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional “aberrant” epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (Scgb1a1-CreER–traced) progenitors and exhibited transcriptional programs of Hif2a activation. In mice treated with repetitive intratracheal bleomycin, deletion of Epas1 (Hif2a) but not Hif1a, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases.
{"title":"Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models","authors":"A. Scott McCall, Sergey Gutor, Hari Tanjore, Ankita Burman, Taylor Sherrill, Micah Chapman, Carla L. Calvi, David Han, Jane Camarata, Raphael P. Hunt, David Nichols, Nicholas E. Banovich, William E. Lawson, Jason J. Gokey, Jonathan A. Kropski, Timothy S. Blackwell","doi":"10.1126/scitranslmed.adk8623","DOIUrl":"10.1126/scitranslmed.adk8623","url":null,"abstract":"<div >Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional “aberrant” epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (<i>Scgb1a1-CreER</i>–traced) progenitors and exhibited transcriptional programs of <i>Hif2a</i> activation. In mice treated with repetitive intratracheal bleomycin, deletion of <i>Epas1</i> (Hif2a) but not <i>Hif1a</i>, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935872","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}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adn9832
Mona Mohammadhosseini, Trevor Enright, Adam Duvall, Alex Chitsazan, Hsin-Yun Lin, Aysegul Ors, Brett A. Davis, Olga Nikolova, Erica Bresciani, Jamie Diemer, Kathleen Craft, Ana Catarina Menezes, Matthew Merguerian, Shawn Chong, Katherine R. Calvo, Natalie T. Deuitch, Shira Glushakow-Smith, Kira Gritsman, Lucy A. Godley, Marshall S. Horwitz, Sioban Keel, Lucio H. Castilla, Emek Demir, Hisham Mohammed, Paul Liu, Anupriya Agarwal
Familial platelet disorder (FPD) is associated with germline RUNX1 mutations, establishing a preleukemic state and increasing the risk of developing leukemia. Currently, there are no intervention strategies to prevent leukemia progression. Single-cell RNA sequencing (n = 10) combined with functional analysis of samples from patients with RUNX1-FPD (n > 75) revealed that FPD hematopoietic stem and progenitor cells (HSPCs) displayed increased myeloid differentiation and suppressed megakaryopoiesis because of increased activation of prosurvival and inflammatory pathways. Bone marrow from patients with RUNX1-FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. RUNX1-FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with RUNX1-FPD showed high transcript and protein expression of CD74 at the preleukemic stage compared with that of healthy controls, which remained high upon patient transformation into leukemia. Further, CD74-mediated signaling was exaggerated in RUNX1-FPD HSPCs compared with healthy controls, leading to the activation of mTOR and JAK/STAT pathways with increased cytokine production. Genetic and pharmacological targeting of CD74 with ISO-1 and its downstream targets JAK1/2 and mTOR reversed RUNX1-FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in RUNX1-FPD pathogenesis, and CD74 signaling is one of the drivers of this inflammation. The repurposing of JAK1/2i (ruxolitinib) and mTORi (sirolimus) and promoting the advancement of CD74 inhibitors in clinical settings as an early intervention strategy would be beneficial to improve the phenotype of patients with RUNX1-FPD and prevent myeloid progression.
{"title":"Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1-familial platelet disorder","authors":"Mona Mohammadhosseini, Trevor Enright, Adam Duvall, Alex Chitsazan, Hsin-Yun Lin, Aysegul Ors, Brett A. Davis, Olga Nikolova, Erica Bresciani, Jamie Diemer, Kathleen Craft, Ana Catarina Menezes, Matthew Merguerian, Shawn Chong, Katherine R. Calvo, Natalie T. Deuitch, Shira Glushakow-Smith, Kira Gritsman, Lucy A. Godley, Marshall S. Horwitz, Sioban Keel, Lucio H. Castilla, Emek Demir, Hisham Mohammed, Paul Liu, Anupriya Agarwal","doi":"10.1126/scitranslmed.adn9832","DOIUrl":"10.1126/scitranslmed.adn9832","url":null,"abstract":"<div >Familial platelet disorder (FPD) is associated with germline <i>RUNX1</i> mutations, establishing a preleukemic state and increasing the risk of developing leukemia. Currently, there are no intervention strategies to prevent leukemia progression. Single-cell RNA sequencing (<i>n</i> = 10) combined with functional analysis of samples from patients with <i>RUNX1</i>-FPD (<i>n</i> > 75) revealed that FPD hematopoietic stem and progenitor cells (HSPCs) displayed increased myeloid differentiation and suppressed megakaryopoiesis because of increased activation of prosurvival and inflammatory pathways. Bone marrow from patients with <i>RUNX1</i>-FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. <i>RUNX1</i>-FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with <i>RUNX1</i>-FPD showed high transcript and protein expression of CD74 at the preleukemic stage compared with that of healthy controls, which remained high upon patient transformation into leukemia. Further, CD74-mediated signaling was exaggerated in <i>RUNX1</i>-FPD HSPCs compared with healthy controls, leading to the activation of mTOR and JAK/STAT pathways with increased cytokine production. Genetic and pharmacological targeting of CD74 with ISO-1 and its downstream targets JAK1/2 and mTOR reversed <i>RUNX1</i>-FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in <i>RUNX1</i>-FPD pathogenesis, and CD74 signaling is one of the drivers of this inflammation. The repurposing of JAK1/2i (ruxolitinib) and mTORi (sirolimus) and promoting the advancement of CD74 inhibitors in clinical settings as an early intervention strategy would be beneficial to improve the phenotype of patients with <i>RUNX1</i>-FPD and prevent myeloid progression.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935875","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}
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