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Lipid-nanoparticle-mediated base editing of the trabecular meshwork rescues glaucoma in vivo. 脂质纳米颗粒介导的小梁网碱基编辑在体内拯救青光眼。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-09 DOI: 10.1172/jci.insight.195593
Balasankara Reddy Kaipa, Linya Li, Prakadeeswari Gopalakrishnan, Samuel Du, Jiin Felgner, Krzysztof Palczewski, Philip Felgner, Gulab S Zode

Mutations in MYOC, the most common genetic cause of glaucoma, cause misfolded myocilin to accumulate in the endoplasmic reticulum (ER), leading to trabecular meshwork (TM) dysfunction, elevated intraocular pressure, and progressive vision loss. While gene editing offers curative potential, current delivery methods rely on viral vectors, which are limited by inflammation, off-target effects, and poor translatability. Here, we report a nonviral lipid nanoparticle (LNP) platform that enables selective in vivo delivery of mRNA encoding an adenine base editor and single guide RNA (LNP-ABE) to TM cells. A direct comparison of LNP-mCherry with lentiviral GFP revealed that LNPs outperform viral vectors, achieving markedly higher efficiency and greater selectivity for the TM without inducing ocular inflammation. In a Cre-inducible Tg.CreMYOCY437H glaucoma mouse model, LNP-Cre mRNA selectively induced mutant MYOC expression in the TM, faithfully recapitulating key disease features. A single administration of LNP-ABE achieved efficient on-target editing of mutant MYOC, reducing mutant myocilin protein by approximately 46%, decreasing aggregates, alleviating ER stress, and fully rescuing the glaucomatous phenotype in Tg.CreMYOCY437H mice. Importantly, no off-target editing or ocular toxicity was detected. These findings establish LNP-based mRNA delivery as a safe, efficient, and clinically translatable approach for TM-targeted genome editing with broad therapeutic potential in glaucoma.

{"title":"Lipid-nanoparticle-mediated base editing of the trabecular meshwork rescues glaucoma in vivo.","authors":"Balasankara Reddy Kaipa, Linya Li, Prakadeeswari Gopalakrishnan, Samuel Du, Jiin Felgner, Krzysztof Palczewski, Philip Felgner, Gulab S Zode","doi":"10.1172/jci.insight.195593","DOIUrl":"https://doi.org/10.1172/jci.insight.195593","url":null,"abstract":"<p><p>Mutations in MYOC, the most common genetic cause of glaucoma, cause misfolded myocilin to accumulate in the endoplasmic reticulum (ER), leading to trabecular meshwork (TM) dysfunction, elevated intraocular pressure, and progressive vision loss. While gene editing offers curative potential, current delivery methods rely on viral vectors, which are limited by inflammation, off-target effects, and poor translatability. Here, we report a nonviral lipid nanoparticle (LNP) platform that enables selective in vivo delivery of mRNA encoding an adenine base editor and single guide RNA (LNP-ABE) to TM cells. A direct comparison of LNP-mCherry with lentiviral GFP revealed that LNPs outperform viral vectors, achieving markedly higher efficiency and greater selectivity for the TM without inducing ocular inflammation. In a Cre-inducible Tg.CreMYOCY437H glaucoma mouse model, LNP-Cre mRNA selectively induced mutant MYOC expression in the TM, faithfully recapitulating key disease features. A single administration of LNP-ABE achieved efficient on-target editing of mutant MYOC, reducing mutant myocilin protein by approximately 46%, decreasing aggregates, alleviating ER stress, and fully rescuing the glaucomatous phenotype in Tg.CreMYOCY437H mice. Importantly, no off-target editing or ocular toxicity was detected. These findings establish LNP-based mRNA delivery as a safe, efficient, and clinically translatable approach for TM-targeted genome editing with broad therapeutic potential in glaucoma.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 3","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142424","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
Myokine SIRPα exacerbates kidney disease in diabetes. 肌细胞因子SIRPα加重糖尿病肾病。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-09 DOI: 10.1172/jci.insight.183392
Jiao Wu, Elisa Russo, Daniela Verzola, Qingtian Li, Helena Zhang, Bhuvaneswari Krishnan, David Sheikh-Hamad, Zhaoyong Hu, William E Mitch, Sandhya S Thomas

Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced intramuscular fat deposition when compared with flox mice on HFD. Moreover, mSIRPα-KO mice displayed enhanced kidney tubular fatty acid oxidation (FAO) expression with suppressed intraorgan triglycerides deposition, and importantly, protection against DKD. Conversely, exogenous SIRPα impaired kidney proximal tubular cell FAO, ATP production, and exacerbated fibrosis. Finally, suppressing SIRPα in skeletal muscles or treatment with anti-SIRPα monoclonal antibodies in STZ-treated mice mitigated cachexia, hyperlipidemia, kidney triglyceride deposition, and renal dysfunction in spite of significant hyperglycemia. Importantly, serum SIRPα was upregulated in patients with DKD. In conclusion, SIRPα serves as a potential biomarker and therapeutic target in DKD.

{"title":"Myokine SIRPα exacerbates kidney disease in diabetes.","authors":"Jiao Wu, Elisa Russo, Daniela Verzola, Qingtian Li, Helena Zhang, Bhuvaneswari Krishnan, David Sheikh-Hamad, Zhaoyong Hu, William E Mitch, Sandhya S Thomas","doi":"10.1172/jci.insight.183392","DOIUrl":"https://doi.org/10.1172/jci.insight.183392","url":null,"abstract":"<p><p>Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced intramuscular fat deposition when compared with flox mice on HFD. Moreover, mSIRPα-KO mice displayed enhanced kidney tubular fatty acid oxidation (FAO) expression with suppressed intraorgan triglycerides deposition, and importantly, protection against DKD. Conversely, exogenous SIRPα impaired kidney proximal tubular cell FAO, ATP production, and exacerbated fibrosis. Finally, suppressing SIRPα in skeletal muscles or treatment with anti-SIRPα monoclonal antibodies in STZ-treated mice mitigated cachexia, hyperlipidemia, kidney triglyceride deposition, and renal dysfunction in spite of significant hyperglycemia. Importantly, serum SIRPα was upregulated in patients with DKD. In conclusion, SIRPα serves as a potential biomarker and therapeutic target in DKD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 3","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142405","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
UHRF1 deficiency exacerbates intestinal inflammation by epigenetic modulation of NPY1R gene methylation. UHRF1缺乏通过表观遗传调节NPY1R基因甲基化加剧肠道炎症。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-09 DOI: 10.1172/jci.insight.190894
Yanan Han, Lina Sun, Yanxing Liu, Xiaohui Zhang, Hao Liu, Haohao Zhang, Xiaoxia Ren, Fenfan Wang, Huafeng Fan, Jie Chen, Dan Liu, Daiming Fan, Yuanyuan Lu, Xue Bai, Ying Fang, Kaichun Wu, Xiaodi Zhao

Epigenetic modifications play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) by mediating gene-environment interactions. We previously showed that UHRF1, a central regulator of DNA methylation, contributes to cancer progression; however, its function in IBD remains poorly understood. Here, we revealed that UHRF1 was frequently reduced in inflamed tissues of patients with IBD and that its deficiency exacerbated intestinal epithelial cell (IEC) damage. Through a multilevel approach incorporating human cell models and an intestinal epithelial-specific Uhrf1-KO mouse model, we established UHRF1 as a key mitigator of IBD progression. Mechanistically, UHRF1 bound to the NPY1R promoter, promoted its methylation, and led to transcriptional suppression. The NPY1R upregulation resulting from UHRF1 deficiency attenuated cAMP/PKA/CREB signaling in IECs, thereby enhancing NF-κB activation and subsequent proinflammatory responses, which compromised intestinal epithelial barrier integrity. Furthermore, we identified miR-141 as a negative regulator of NPY1R, highlighting its potential as a therapeutic agent. Collectively, our results identified the UHRF1/NPY1R regulatory axis as a critical epigenetic mechanism in intestinal inflammation and underscored its dual promise for IBD diagnostics and therapy.

{"title":"UHRF1 deficiency exacerbates intestinal inflammation by epigenetic modulation of NPY1R gene methylation.","authors":"Yanan Han, Lina Sun, Yanxing Liu, Xiaohui Zhang, Hao Liu, Haohao Zhang, Xiaoxia Ren, Fenfan Wang, Huafeng Fan, Jie Chen, Dan Liu, Daiming Fan, Yuanyuan Lu, Xue Bai, Ying Fang, Kaichun Wu, Xiaodi Zhao","doi":"10.1172/jci.insight.190894","DOIUrl":"https://doi.org/10.1172/jci.insight.190894","url":null,"abstract":"<p><p>Epigenetic modifications play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) by mediating gene-environment interactions. We previously showed that UHRF1, a central regulator of DNA methylation, contributes to cancer progression; however, its function in IBD remains poorly understood. Here, we revealed that UHRF1 was frequently reduced in inflamed tissues of patients with IBD and that its deficiency exacerbated intestinal epithelial cell (IEC) damage. Through a multilevel approach incorporating human cell models and an intestinal epithelial-specific Uhrf1-KO mouse model, we established UHRF1 as a key mitigator of IBD progression. Mechanistically, UHRF1 bound to the NPY1R promoter, promoted its methylation, and led to transcriptional suppression. The NPY1R upregulation resulting from UHRF1 deficiency attenuated cAMP/PKA/CREB signaling in IECs, thereby enhancing NF-κB activation and subsequent proinflammatory responses, which compromised intestinal epithelial barrier integrity. Furthermore, we identified miR-141 as a negative regulator of NPY1R, highlighting its potential as a therapeutic agent. Collectively, our results identified the UHRF1/NPY1R regulatory axis as a critical epigenetic mechanism in intestinal inflammation and underscored its dual promise for IBD diagnostics and therapy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 3","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142494","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
Tracing the molecular route to progression in miRNA-biogenesis-defective thyroid lesions. 追踪mirna -生物发生-甲状腺缺陷病变进展的分子途径。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-09 DOI: 10.1172/jci.insight.198338
Anne-Sophie Chong, Carla Roca, Paula Morales-Sánchez, Eduard Dorca, Verónica Barea, Ignacio Ruz-Caracuel, Pablo Valderrabano, Carlota Rovira, Cristina Jou, Dorothée Bouron-Dal Soglio, Rebecca D Chernock, Giovana T Torrezan, Marc Pusztaszeri, José M Cameselle-Teijeiro, Xavier Matias-Guiu, Clara V Alvarez, Héctor Salvador, Jonathan D Wasserman, Luis Javier Leandro-García, William D Foulkes, Eduardo Andrés-León, Paula Casano-Sancho, Barbara Rivera

Germline and somatic changes in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1- and DGCR8-mutated thyroid lesions using multiomic profiling on over 30 DICER1-/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic changes, which when combined with enhanced downregulation of miRNAs distinguished DICER1-/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA-encoding genes characterized DICER1-/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related changes. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis-related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.

{"title":"Tracing the molecular route to progression in miRNA-biogenesis-defective thyroid lesions.","authors":"Anne-Sophie Chong, Carla Roca, Paula Morales-Sánchez, Eduard Dorca, Verónica Barea, Ignacio Ruz-Caracuel, Pablo Valderrabano, Carlota Rovira, Cristina Jou, Dorothée Bouron-Dal Soglio, Rebecca D Chernock, Giovana T Torrezan, Marc Pusztaszeri, José M Cameselle-Teijeiro, Xavier Matias-Guiu, Clara V Alvarez, Héctor Salvador, Jonathan D Wasserman, Luis Javier Leandro-García, William D Foulkes, Eduardo Andrés-León, Paula Casano-Sancho, Barbara Rivera","doi":"10.1172/jci.insight.198338","DOIUrl":"https://doi.org/10.1172/jci.insight.198338","url":null,"abstract":"<p><p>Germline and somatic changes in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1- and DGCR8-mutated thyroid lesions using multiomic profiling on over 30 DICER1-/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic changes, which when combined with enhanced downregulation of miRNAs distinguished DICER1-/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA-encoding genes characterized DICER1-/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related changes. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis-related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 3","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142534","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
Spatial transcriptomics identifies differentiation, lipid metabolism, and retinoid pathway alterations in acne vulgaris. 空间转录组学鉴定寻常痤疮的分化、脂质代谢和类视黄醇途径改变。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-09 DOI: 10.1172/jci.insight.198021
Joseph S Durgin, Natalia A Veniaminova, Thomas J Huyge, Shih-Ying Tsai, Jennifer Fox, Yuli Cai, Mrinal K Sarkar, Lam C Tsoi, Johann E Gudjonsson, Sunny Y Wong

Acne vulgaris is a common skin condition involving complex interactions among lipid-secreting sebaceous glands, keratinocytes, immune cells, and microbiota. While retinoids are effective for treating acne, disease pathogenesis remains poorly understood. In particular, it remains unclear how different subtypes of acne, including inflammatory (pustular) and noninflammatory (comedonal) lesions, vary in gene expression, signaling, and sebaceous gland involvement. Here, we performed spatial transcriptomics on healthy, nonlesional, comedonal, and pustular acne skin using a custom panel targeting sebaceous differentiation, lipid metabolism, and retinoid signaling pathways. We also designed a specialized segmentation pipeline to improve transcript assignment in the spatially complex sebaceous gland. Our analyses identified a PPARG+ transitional basal cell state in sebocytes and revealed that comedonal skin upregulates sebogenesis genes, whereas pustular skin downregulates sebogenesis. Both lesion types exhibited increased AP-1 transcription factors and elevated FABP5, a chaperone that blunts retinoic acid receptor signaling. Finally, we demonstrated that an AP-1 inhibitor, T-5224, downregulates FABP5 in human keratinocytes and reduces pustule formation in a mouse model of high-fat diet-induced folliculitis. Altogether, these findings indicate that altered lipogenesis, retinoid signaling, and keratinocyte differentiation are key features of acne, and nominate AP-1 and FABP5 as potential therapeutic targets.

{"title":"Spatial transcriptomics identifies differentiation, lipid metabolism, and retinoid pathway alterations in acne vulgaris.","authors":"Joseph S Durgin, Natalia A Veniaminova, Thomas J Huyge, Shih-Ying Tsai, Jennifer Fox, Yuli Cai, Mrinal K Sarkar, Lam C Tsoi, Johann E Gudjonsson, Sunny Y Wong","doi":"10.1172/jci.insight.198021","DOIUrl":"https://doi.org/10.1172/jci.insight.198021","url":null,"abstract":"<p><p>Acne vulgaris is a common skin condition involving complex interactions among lipid-secreting sebaceous glands, keratinocytes, immune cells, and microbiota. While retinoids are effective for treating acne, disease pathogenesis remains poorly understood. In particular, it remains unclear how different subtypes of acne, including inflammatory (pustular) and noninflammatory (comedonal) lesions, vary in gene expression, signaling, and sebaceous gland involvement. Here, we performed spatial transcriptomics on healthy, nonlesional, comedonal, and pustular acne skin using a custom panel targeting sebaceous differentiation, lipid metabolism, and retinoid signaling pathways. We also designed a specialized segmentation pipeline to improve transcript assignment in the spatially complex sebaceous gland. Our analyses identified a PPARG+ transitional basal cell state in sebocytes and revealed that comedonal skin upregulates sebogenesis genes, whereas pustular skin downregulates sebogenesis. Both lesion types exhibited increased AP-1 transcription factors and elevated FABP5, a chaperone that blunts retinoic acid receptor signaling. Finally, we demonstrated that an AP-1 inhibitor, T-5224, downregulates FABP5 in human keratinocytes and reduces pustule formation in a mouse model of high-fat diet-induced folliculitis. Altogether, these findings indicate that altered lipogenesis, retinoid signaling, and keratinocyte differentiation are key features of acne, and nominate AP-1 and FABP5 as potential therapeutic targets.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 3","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142552","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
Plakoglobin phosphorylation at serine 665 is capable of stabilizing cadherin-mediated adhesion in keratinocytes. 丝氨酸665位点的血小板蛋白磷酸化能够稳定角化细胞中钙粘蛋白介导的粘附。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-09 DOI: 10.1172/jci.insight.190359
Franziska Vielmuth, Anna M Sigmund, Desalegn T Egu, Matthias Hiermaier, Letyfee S Steinert, Sina Moztarzadeh, Mariia Klimkina, Margarethe Ec Schikora, Paulina M Rion, Thomas Schmitt, Katharina Meier, Kamran Ghoreschi, Anja Ke Horn, Mariya Y Radeva, Daniela Kugelmann, Jens Waschke

In pemphigus, autoantibodies against the desmosomal cadherins desmoglein (DSG) DSG1 and DSG3 cause intraepidermal blistering. Recently, we found that increasing cAMP with the phosphodiesterase-4 inhibitor apremilast stabilizes keratinocyte cohesion in pemphigus. This effect is paralleled by phosphorylation of the desmosomal plaque protein plakoglobin (PG) at serine 665 (S665). Here, we investigated the relevance of PG phosphorylation at S665 for stabilization of keratinocyte cohesion and further characterized the underlying mechanisms. Ultrastructural analysis of a recently established PG-S665 phospho-deficient mouse model (PG-S665A) showed diminished keratin insertion. Accordingly, the protective effect of apremilast against pemphigus autoantibody-induced skin blistering was diminished, and apremilast failed to restore alterations of the keratin cytoskeleton in PG-S665A mice. Keratinocytes derived from PG-S665A mice revealed a disorganized keratin cytoskeleton and reduced single-molecule binding strength of DSG3. In line with this, in ex vivo human skin, increased cAMP augmented keratin insertion into desmosomal plaques. Additionally, PG phosphorylated at S665 colocalized with desmoplakin and keratin filaments anchoring to desmosomes and increased cAMP-accelerated assembly of desmosomes. Taken together, phosphorylation of PG at S665 was crucial for protective effects of apremilast in pemphigus and for maintenance of DSG3 binding and keratin filament anchorage to desmosomes.

{"title":"Plakoglobin phosphorylation at serine 665 is capable of stabilizing cadherin-mediated adhesion in keratinocytes.","authors":"Franziska Vielmuth, Anna M Sigmund, Desalegn T Egu, Matthias Hiermaier, Letyfee S Steinert, Sina Moztarzadeh, Mariia Klimkina, Margarethe Ec Schikora, Paulina M Rion, Thomas Schmitt, Katharina Meier, Kamran Ghoreschi, Anja Ke Horn, Mariya Y Radeva, Daniela Kugelmann, Jens Waschke","doi":"10.1172/jci.insight.190359","DOIUrl":"https://doi.org/10.1172/jci.insight.190359","url":null,"abstract":"<p><p>In pemphigus, autoantibodies against the desmosomal cadherins desmoglein (DSG) DSG1 and DSG3 cause intraepidermal blistering. Recently, we found that increasing cAMP with the phosphodiesterase-4 inhibitor apremilast stabilizes keratinocyte cohesion in pemphigus. This effect is paralleled by phosphorylation of the desmosomal plaque protein plakoglobin (PG) at serine 665 (S665). Here, we investigated the relevance of PG phosphorylation at S665 for stabilization of keratinocyte cohesion and further characterized the underlying mechanisms. Ultrastructural analysis of a recently established PG-S665 phospho-deficient mouse model (PG-S665A) showed diminished keratin insertion. Accordingly, the protective effect of apremilast against pemphigus autoantibody-induced skin blistering was diminished, and apremilast failed to restore alterations of the keratin cytoskeleton in PG-S665A mice. Keratinocytes derived from PG-S665A mice revealed a disorganized keratin cytoskeleton and reduced single-molecule binding strength of DSG3. In line with this, in ex vivo human skin, increased cAMP augmented keratin insertion into desmosomal plaques. Additionally, PG phosphorylated at S665 colocalized with desmoplakin and keratin filaments anchoring to desmosomes and increased cAMP-accelerated assembly of desmosomes. Taken together, phosphorylation of PG at S665 was crucial for protective effects of apremilast in pemphigus and for maintenance of DSG3 binding and keratin filament anchorage to desmosomes.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 3","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142479","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
Selective SIK2/SIK3 inhibition reprograms pro- and antiinflammatory pathways in myeloid cells, improving autoimmune disease outcomes. 选择性SIK2/SIK3抑制重编程骨髓细胞的促炎和抗炎通路,改善自身免疫性疾病的结果。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-09 DOI: 10.1172/jci.insight.171776
Steve De Vos, Nicolas Desroy, Susan J Bellaire, Anna Pereira Fernandes, Stéphanie Lavazais, Didier Merciris, Carole Delachaume, Catherine Robin-Jagerschmidt, Adrien Cosson, Angela Lazaryan, Nancy Van Osselaer, David Amantini, Christophe Peixoto, Maikel L Colli, Thomas Van Eeckhoutte, Tiina Hakonen, Magali Constant, Alberto Garcia-Hernandez, Rahul Barron, Geert D'Haens, Wulf O Böcher

Adaptive immune responses are widely considered the primary drivers of chronic inflammation in autoimmune disease, yet increasing evidence suggests that dysregulated myeloid cells play a central role in sustaining tissue damage. Salt-inducible kinases (SIKs) regulate immune cell activation, and their pharmacological inhibition can promote a shift from proinflammatory toward an immunoregulatory phenotype. We investigated whether selective inhibition of SIK2 and SIK3 with GLPG3970 could reprogram monocytes, macrophages, and dendritic cells, and we assessed pharmacological effects on activated T and B cells. Preclinical studies in mouse models of colitis, psoriasis, and arthritis demonstrated that SIK2/SIK3 inhibition reduced inflammatory activity and promoted immunoregulatory and tolerogenic-associated pathways. Clinical signal-detection studies in ulcerative colitis, psoriasis, and rheumatoid arthritis revealed signs of clinical and biological activity in ulcerative colitis and psoriasis. These findings suggest that myeloid cell dysfunction and impaired myeloid phenotype switching contribute to chronic inflammation in autoimmune diseases and that therapeutic targeting of SIK2/SIK3 holds the potential to restore immune balance by converting proinflammatory into regulatory pathways. Collectively, this work supports SIK2/SIK3 inhibition as a potential treatment strategy for myeloid cell-driven chronic inflammatory conditions.

{"title":"Selective SIK2/SIK3 inhibition reprograms pro- and antiinflammatory pathways in myeloid cells, improving autoimmune disease outcomes.","authors":"Steve De Vos, Nicolas Desroy, Susan J Bellaire, Anna Pereira Fernandes, Stéphanie Lavazais, Didier Merciris, Carole Delachaume, Catherine Robin-Jagerschmidt, Adrien Cosson, Angela Lazaryan, Nancy Van Osselaer, David Amantini, Christophe Peixoto, Maikel L Colli, Thomas Van Eeckhoutte, Tiina Hakonen, Magali Constant, Alberto Garcia-Hernandez, Rahul Barron, Geert D'Haens, Wulf O Böcher","doi":"10.1172/jci.insight.171776","DOIUrl":"https://doi.org/10.1172/jci.insight.171776","url":null,"abstract":"<p><p>Adaptive immune responses are widely considered the primary drivers of chronic inflammation in autoimmune disease, yet increasing evidence suggests that dysregulated myeloid cells play a central role in sustaining tissue damage. Salt-inducible kinases (SIKs) regulate immune cell activation, and their pharmacological inhibition can promote a shift from proinflammatory toward an immunoregulatory phenotype. We investigated whether selective inhibition of SIK2 and SIK3 with GLPG3970 could reprogram monocytes, macrophages, and dendritic cells, and we assessed pharmacological effects on activated T and B cells. Preclinical studies in mouse models of colitis, psoriasis, and arthritis demonstrated that SIK2/SIK3 inhibition reduced inflammatory activity and promoted immunoregulatory and tolerogenic-associated pathways. Clinical signal-detection studies in ulcerative colitis, psoriasis, and rheumatoid arthritis revealed signs of clinical and biological activity in ulcerative colitis and psoriasis. These findings suggest that myeloid cell dysfunction and impaired myeloid phenotype switching contribute to chronic inflammation in autoimmune diseases and that therapeutic targeting of SIK2/SIK3 holds the potential to restore immune balance by converting proinflammatory into regulatory pathways. Collectively, this work supports SIK2/SIK3 inhibition as a potential treatment strategy for myeloid cell-driven chronic inflammatory conditions.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 3","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142482","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
Endothelial oncogenic KRAS mutation drives the dynamics of microglia and macrophages in brain arteriovenous malformation. 内皮癌性KRAS突变驱动脑动静脉畸形中小胶质细胞和巨噬细胞的动态。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-05 DOI: 10.1172/jci.insight.195638
Hyejin Park, Jung-Eun Park, Bridger H Freeman, Bosco Seong Kyu Yang, Shun-Ming Ting, Alexander K Suh, Jude Pj Savarraj, Shuning Huang, Jakob Körbelin, Huimahn Alex Choi, Sean P Marrelli, Jaroslaw Aronowski, Peng Roc Chen, Eunhee Kim, Eun S Park

Mutation of KRAS in endothelial cells (KRAS-EC) leads to intracerebral hemorrhage (ICH) in brain arteriovenous malformations (bAVM), resulting in severe disabilities or even death. However, it is unclear what causes this hemorrhagic conversion of bAVM. Here, using a locally established, clinically-relevant sporadic bAVM mouse model, created by overexpressing mutant KRAS (KRASG12V) in the brain EC, we demonstrate that KRAS-EC act as trigger for microglia (MG) activation and infiltration of macrophages (Mϕ). Using three-dimensional immunostaining approach with cleared human and mouse bAVM tissues, we demonstrate an abundance of MG/Mϕ around the bAVM nidus. The presence of MG/Mϕ are correlated to the blood-brain barrier leakage in bAVM area. Time-lapsed intravital imaging in Cx3cr1-gfp;Ccr2-rfp reporter mice demonstrate the dynamic activation of MG and infiltration of Mϕ toward mutant KRAS-modified dysplastic vessels. Importantly, a time course analysis showed that these activated/infiltrated MG/Mϕ are present around the bAVMs prior to hemorrhagic conversion, and controlled depletion of MG/Mϕ reduced ICH incidence in bAVM. Inhibition of MG/Mϕ with long-term minocycline treatment attenuated the incidence of ICHs around bAVMs. Our study indicates that MG/Mϕ are involved in destabilization of KRAS-induced bAVM, leading to hemorrhagic conversion/ICH. Thus, modulation of MG/Mϕ may reduce ICH risk in bAVM patients.

{"title":"Endothelial oncogenic KRAS mutation drives the dynamics of microglia and macrophages in brain arteriovenous malformation.","authors":"Hyejin Park, Jung-Eun Park, Bridger H Freeman, Bosco Seong Kyu Yang, Shun-Ming Ting, Alexander K Suh, Jude Pj Savarraj, Shuning Huang, Jakob Körbelin, Huimahn Alex Choi, Sean P Marrelli, Jaroslaw Aronowski, Peng Roc Chen, Eunhee Kim, Eun S Park","doi":"10.1172/jci.insight.195638","DOIUrl":"https://doi.org/10.1172/jci.insight.195638","url":null,"abstract":"<p><p>Mutation of KRAS in endothelial cells (KRAS-EC) leads to intracerebral hemorrhage (ICH) in brain arteriovenous malformations (bAVM), resulting in severe disabilities or even death. However, it is unclear what causes this hemorrhagic conversion of bAVM. Here, using a locally established, clinically-relevant sporadic bAVM mouse model, created by overexpressing mutant KRAS (KRASG12V) in the brain EC, we demonstrate that KRAS-EC act as trigger for microglia (MG) activation and infiltration of macrophages (Mϕ). Using three-dimensional immunostaining approach with cleared human and mouse bAVM tissues, we demonstrate an abundance of MG/Mϕ around the bAVM nidus. The presence of MG/Mϕ are correlated to the blood-brain barrier leakage in bAVM area. Time-lapsed intravital imaging in Cx3cr1-gfp;Ccr2-rfp reporter mice demonstrate the dynamic activation of MG and infiltration of Mϕ toward mutant KRAS-modified dysplastic vessels. Importantly, a time course analysis showed that these activated/infiltrated MG/Mϕ are present around the bAVMs prior to hemorrhagic conversion, and controlled depletion of MG/Mϕ reduced ICH incidence in bAVM. Inhibition of MG/Mϕ with long-term minocycline treatment attenuated the incidence of ICHs around bAVMs. Our study indicates that MG/Mϕ are involved in destabilization of KRAS-induced bAVM, leading to hemorrhagic conversion/ICH. Thus, modulation of MG/Mϕ may reduce ICH risk in bAVM patients.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124960","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
Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone. 纳洛酮不能完全逆转芬太尼诱导的酒精呼吸抑制的增强作用。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-03 DOI: 10.1172/jci.insight.198059
Emma V Frye, Lyndsay E Hastings, Aniah N Matthews, Adriana Gregory-Flores, Janaina Cm Vendruscolo, Lindsay A Kryszak, Shelley N Jackson, Aidan J Hampson, Nora D Volkow, Leandro F Vendruscolo, Renata Cn Marchette, George F Koob

The high frequency of opioid overdose deaths often involves co-use of alcohol, which is reported in approximately 30% of fentanyl fatalities. Both substances depress respiratory function, and their combined effects can be lethal. The present study investigated physiological parameters of respiratory-depressant effects of fentanyl when co-administered with alcohol and its sensitivity to naloxone reversal using whole-body plethysmography in male and female Long-Evans rats. Administration of a high, sedative-like dose of alcohol alone or fentanyl alone resulted in no mortality, but fentanyl+alcohol led to mortality rates of 42% and 33% in females and males, respectively. The fentanyl+alcohol combination reduced minute ventilation and increased apneic pauses compared with either drug alone. Lower, binge-like alcohol doses, when combined with fentanyl, also amplified respiratory depression. Pretreatment with naloxone did not fully restore normal respiration. Naloxone administered after fentanyl+alcohol transiently reversed the decrease in minute ventilation but did not reverse apneic pauses. Fentanyl-dependent rats were partially tolerant to fentanyl- and fentanyl+alcohol-induced respiratory depression, but alcohol-dependent rats exhibited sensitization to alcohol- and fentanyl+alcohol-induced apnea. These findings highlight physiological parameters of severe respiratory risks with fentanyl+alcohol co-use, which are inadequately reversed by naloxone, underscoring the need for targeted strategies to manage opioid+alcohol overdoses.

阿片类药物过量死亡的高频率通常涉及酒精的共同使用,据报告,芬太尼死亡中约有30%是酒精。这两种物质都会抑制呼吸功能,它们的联合作用可能是致命的。本研究利用全身容积描图研究了芬太尼与酒精共给药时呼吸抑制作用的生理参数及其对纳洛酮逆转的敏感性。单独使用高剂量的类似镇静剂的酒精或单独使用芬太尼均未导致死亡,但芬太尼+酒精在女性和男性中分别导致42%和33%的死亡率。与单独使用任何一种药物相比,芬太尼+酒精联合使用减少了通气时间,增加了呼吸暂停时间。当与芬太尼联合使用时,较低的、类似狂欢的酒精剂量也会加剧呼吸抑制。纳洛酮预处理不能完全恢复正常呼吸。芬太尼+酒精后给予纳洛酮短暂逆转了分钟通气的减少,但没有逆转呼吸暂停。芬太尼依赖大鼠对芬太尼和芬太尼+酒精诱导的呼吸抑制部分耐受,但酒精依赖大鼠对酒精和芬太尼+酒精诱导的呼吸暂停表现出敏感性。这些发现突出了芬太尼+酒精共同使用时严重呼吸风险的生理参数,而纳洛酮不能充分扭转这些生理参数,强调需要有针对性的策略来管理阿片类药物+酒精过量。
{"title":"Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone.","authors":"Emma V Frye, Lyndsay E Hastings, Aniah N Matthews, Adriana Gregory-Flores, Janaina Cm Vendruscolo, Lindsay A Kryszak, Shelley N Jackson, Aidan J Hampson, Nora D Volkow, Leandro F Vendruscolo, Renata Cn Marchette, George F Koob","doi":"10.1172/jci.insight.198059","DOIUrl":"https://doi.org/10.1172/jci.insight.198059","url":null,"abstract":"<p><p>The high frequency of opioid overdose deaths often involves co-use of alcohol, which is reported in approximately 30% of fentanyl fatalities. Both substances depress respiratory function, and their combined effects can be lethal. The present study investigated physiological parameters of respiratory-depressant effects of fentanyl when co-administered with alcohol and its sensitivity to naloxone reversal using whole-body plethysmography in male and female Long-Evans rats. Administration of a high, sedative-like dose of alcohol alone or fentanyl alone resulted in no mortality, but fentanyl+alcohol led to mortality rates of 42% and 33% in females and males, respectively. The fentanyl+alcohol combination reduced minute ventilation and increased apneic pauses compared with either drug alone. Lower, binge-like alcohol doses, when combined with fentanyl, also amplified respiratory depression. Pretreatment with naloxone did not fully restore normal respiration. Naloxone administered after fentanyl+alcohol transiently reversed the decrease in minute ventilation but did not reverse apneic pauses. Fentanyl-dependent rats were partially tolerant to fentanyl- and fentanyl+alcohol-induced respiratory depression, but alcohol-dependent rats exhibited sensitization to alcohol- and fentanyl+alcohol-induced apnea. These findings highlight physiological parameters of severe respiratory risks with fentanyl+alcohol co-use, which are inadequately reversed by naloxone, underscoring the need for targeted strategies to manage opioid+alcohol overdoses.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113469","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
Durable Hematopoiesis and Tolerance After Vertebral Bone Marrow Transplant from a Deceased Lung Transplant Donor. 已故肺移植供者椎体骨髓移植后的持久造血和耐受性。
IF 6.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-03 DOI: 10.1172/jci.insight.198029
Paul Szabolcs, Xiaohua Chen, Marian G Michaels, Memphis Hill, Evelyn Garchar, Zarreen Amin, Heather M Stanczak, Shawna McIntyre, Aleksandra Petrovic, Dhivyaa Rajasundaram, Ansuman Chattopadhyay, Jonathan E Spahr, Peter D Wearden, Geoffrey Kurland

We hypothesized that performing bone marrow transplant (BMT) using marrow extracted from the vertebral bodies (VB) of an unrelated deceased lung transplant (LTX) donor would be able to establish persistent hematopoiesis, generate immunity, and tolerance. A teenager with severe combined immunodeficiency with lung failure due to recurrent pneumonias underwent LTX in 2016 from a 1/8 HLA allele-matched unrelated donor, followed by BMT 4 months later using T-cell/B-cell-depleted, cryopreserved VB marrow. Rapid engraftment was followed by accelerating immune competence at 6 months, with independence from immunosuppression by 16 months. Donor T-cell (>95%) and myeloid chimerism (7-10%) have persisted for over nine years. At two years post-BMT, circulating T cells were hyporesponsive to host dendritic cells in vitro. T-cell receptor clonotyping revealed the disappearance of host-reactive clones, and T-cell RNA-sequencing exhibited downmodulated signaling pathways for cytotoxicity/rejection, paired with upregulated immunomodulatory pathways, suggesting active suppression. In parallel, host monocytes upregulated certain signaling pathways, indicating active interactions between post-thymic donor T cells and host monocytes. In summary, durable hematopoietic engraftment, immunity, and tolerance were demonstrable for the first time in a recipient of BMT obtained from VB graft.

我们假设骨髓移植(BMT)使用从无关的已故肺移植(LTX)供者的椎体(VB)中提取的骨髓能够建立持久的造血功能,产生免疫力和耐受性。2016年,一名患有严重联合免疫缺陷并因复发性肺炎导致肺衰竭的青少年接受了1/8 HLA等位基因匹配的非亲属供体的LTX治疗,4个月后使用t细胞/ b细胞缺失的冷冻保存的VB骨髓进行了BMT治疗。快速植入后,6个月时免疫能力增强,16个月时免疫抑制独立。供体t细胞(>95%)和骨髓嵌合(7-10%)持续超过9年。在bmt后两年,体外循环T细胞对宿主树突状细胞的反应降低。t细胞受体克隆分型显示宿主反应性克隆消失,t细胞rna测序显示细胞毒性/排斥信号通路下调,免疫调节通路上调,提示主动抑制。同时,宿主单核细胞上调某些信号通路,表明胸腺后供体T细胞与宿主单核细胞之间存在积极的相互作用。总之,持久的造血植入、免疫和耐受性首次在VB移植获得的BMT受体中得到证实。
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引用次数: 0
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