JCI insightPub Date : 2026-09-01eCollection Date: 2026-10-08DOI: 10.1172/jci.insight.202419
Katherine A Braun, Nicolas M Garcia, Mohamed A Ahmed, Darleen S Tu, Stephanie I Walter, Emma D Wrenn, Megan Eb Dean, Neerja Katiyar, Elizabeth R Lawlor
{"title":"Menin inhibition impairs metastatic colonization of Ewing sarcoma.","authors":"Katherine A Braun, Nicolas M Garcia, Mohamed A Ahmed, Darleen S Tu, Stephanie I Walter, Emma D Wrenn, Megan Eb Dean, Neerja Katiyar, Elizabeth R Lawlor","doi":"10.1172/jci.insight.202419","DOIUrl":"10.1172/jci.insight.202419","url":null,"abstract":"<p><p>Menin is a scaffolding protein that interacts with context-specific partners to regulate gene expression. In rearranged mixed-lineage leukemia, Menin-MLL interactions drive leukemogenesis and Menin inhibitors have been FDA approved for these cancers. We previously reported that Menin promotes oncogenic phenotypes in Ewing sarcoma (EwS). Here, we sought to define EwS-specific functions of Menin and determine if Menin inhibitors could be therapeutically leveraged for these tumors. Genetic KO of Menin had no effect on EwS cell proliferation in vitro, but metastatic potential of Menin-depleted cells in vivo was impaired. Transcriptional profiling of Menin-KO cells in vitro showed reproducible downregulation of MYC signature genes and upregulation of developmental programs. Conversely, transcriptional rewiring of developmental genes and restoration of MYC target gene expression were evident in tumors that arose from Menin-KO cells. Exposing EwS cells to the Menin inhibitor VTP50469 (revumenib) inhibited expression of MYC targets, and coimmunoprecipitation studies detected Menin-MYC interactions that were partially disrupted by the drug. Metastatic colonization of disseminated EwS cells in vivo was significantly inhibited in mice fed VTP50469 chow. Together these findings implicate Menin as a mediator of EwS metastasis and suggest that Menin inhibitors warrant investigation as novel therapeutics for patients with high-risk disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887662","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}
JCI insightPub Date : 2026-09-01eCollection Date: 2026-10-08DOI: 10.1172/jci.insight.202223
Qian Jiang, Cong Wang, Yuerong Ren, Peiyun Duan, Ke Tian, Xiangwei Duan, Binghan Cai, Changzhong Xu, Ke Liu, Jian Li, Larry Benowitz, Ningli Wang, Bing Jiang, Lili Xie
{"title":"Optic nerve regeneration requires the intracellular domain of LIFRα/CD118.","authors":"Qian Jiang, Cong Wang, Yuerong Ren, Peiyun Duan, Ke Tian, Xiangwei Duan, Binghan Cai, Changzhong Xu, Ke Liu, Jian Li, Larry Benowitz, Ningli Wang, Bing Jiang, Lili Xie","doi":"10.1172/jci.insight.202223","DOIUrl":"10.1172/jci.insight.202223","url":null,"abstract":"<p><p>Identifying factors that govern the ability of retinal ganglion cells (RGCs) to extend axons is an important step in developing therapies to achieve recovery after optic nerve injury. Here, we report that the intracellular domain of the leukemia inhibitory factor receptor (LIFR/CD118) is essential for mature RGCs' ability to regenerate injured axons independent of the cognate ligand (LIF) and other therapies. Overexpression of LIFR in adult RGCs induces neurite outgrowth in cultured RGCs and axon regeneration in vivo while strongly amplifying RGCs' response to LIF itself and to unrelated growth factors. Conversely, downregulation of LIFR strongly suppresses the pro-regenerative effects of PTEN knockdown and other potent stimuli. LIFR modulation alters the constitutive activity of the MAPK pathway, in contrast to LIF itself, which primarily activates pSTAT3. The extracellular domain-truncated LIFR construct retains substantial pro-regenerative activity, whereas mutation of intracellular signaling motifs reduces the full regenerative effect of LIFR. Together, these findings identify LIFR as a key cell-autonomous regulator of optic nerve regeneration in mature RGCs.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873940","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}
JCI insightPub Date : 2026-09-01eCollection Date: 2026-10-08DOI: 10.1172/jci.insight.205826
Sumeet Manandhar, Mohna Bandyopadhyay, Olga A Tkacheva, William J Shufesky, Gregory A Gibson, Simon C Watkins, Adrian E Morelli, Adriana T Larregina
{"title":"Substance P-NK1R signaling of keratinocytes initiates the skin inflammatory environment required for allergic contact dermatitis.","authors":"Sumeet Manandhar, Mohna Bandyopadhyay, Olga A Tkacheva, William J Shufesky, Gregory A Gibson, Simon C Watkins, Adrian E Morelli, Adriana T Larregina","doi":"10.1172/jci.insight.205826","DOIUrl":"10.1172/jci.insight.205826","url":null,"abstract":"<p><p>Allergic contact dermatitis (ACD), a recurrent inflammatory skin disorder, affects 21% of humans and is the second leading cause of occupational diseases in the United States. ACD is initiated by the innate immune response to skin-contact sensitizers potentiated by the neuropeptide substance P (SP). Skin sensitizers stimulate SP-secreting sensory nerves and trigger proinflammatory functions of keratinocytes expressing the neurokinin 1 receptor (NK1R). Nevertheless, the neuroimmune regulation of hapten-initiated skin inflammation remains incompletely elucidated. Using K14Cre/+ NK1RKO mice skin-sensitized with 2,4-dinitrochlorobenzene (DNCB), we demonstrate that NK1R deletion exclusively in keratinocytes prevents hapten-initiated skin inflammation, impairs the mobilization of conventional dendritic cells to draining lymph nodes, and blocks the elicitation of the contact hypersensitivity reaction to the same extent observed in global Tac1KO (without SP) and NK1RKO mice. The DNCB effects were restored by skin co-administration of IL-1β and TNF-α. SP-NK1R signaling of mouse and human keratinocytes increased transcripts encoding proteins of the NLRP3 inflammasome. Although DNCB and SP induced pro-IL-1β synthesis, only SP triggered intracellular Ca2+ increase, NFATc1 nuclear translocation, and synthesis of TNF-α, a cytokine mediating systemic inflammation in ACD. Our data identifying SP-NK1R signaling of keratinocytes as a key mechanism for ACD provide relevant insight for therapies targeting skin neuroimmune interactions.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873975","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}
JCI insightPub Date : 2026-09-01DOI: 10.1172/jci.insight.203119
Stephanie J Hanna, Emma Js Robinson, Terri C Thayer, Maki Nakayama, Laurie Landry, Robert Andrews, Garry Dolton, Joanne Davies, Evangelia Williams, James A Pearson, Andrew K Sewell, Parth Narendran, David Wraith, Alexandra Howell, Philippa Young, Mary Hart, Anton Lindqvist, F Susan Wong, Tim Im Tree, Colin M Dayan, Danijela Tatovic
{"title":"Tracking GAD-specific T-cell expansions in Type 1 diabetes by intradermal GAD-Alum challenge.","authors":"Stephanie J Hanna, Emma Js Robinson, Terri C Thayer, Maki Nakayama, Laurie Landry, Robert Andrews, Garry Dolton, Joanne Davies, Evangelia Williams, James A Pearson, Andrew K Sewell, Parth Narendran, David Wraith, Alexandra Howell, Philippa Young, Mary Hart, Anton Lindqvist, F Susan Wong, Tim Im Tree, Colin M Dayan, Danijela Tatovic","doi":"10.1172/jci.insight.203119","DOIUrl":"https://doi.org/10.1172/jci.insight.203119","url":null,"abstract":"<p><p>Identifying and monitoring autoreactive T cells that drive beta cell destruction remains a major obstacle to developing effective immunotherapies for type 1 diabetes (T1D). These cells are extremely rare in peripheral blood and cannot be accessed directly from the pancreas. We used intradermal injection of Glutamic Acid Decarboxylase (GAD)-Alum to recruit GAD-specific T cells to accessible sites in the skin and skin-draining lymph nodes (LNs), sampled by skin suction blisters and ultrasound-guided LN aspiration. Peripheral blood samples obtained before GAD injection were restimulated with GAD in vitro to detect reactive CD4+ T cells. Single-cell RNA sequencing (scRNAseq) followed by re-expression of selected T cell receptors (TCRs) confirmed antigen specificity. Up to 70% of T cells at the skin injection site were clonally-expanded and 4 of 14 (28%) re-expressed TCRs were GAD-reactive. In LNs 1 of 14 (4%) clonally-expanded TCRs was GAD-reactive, representing ~0.08% of all T-cells. GAD-reactive cells across compartments displayed Th1 and Th17-associated transcription signatures. These results demonstrate the intradermal autoantigen challenge and scRNAseq, enable direct identification and molecular profiling of autoreactive T cells in vivo. This minimally invasive approach provides a powerful platform for tracking antigen-specific T cells to monitor disease activity and evaluate immune interventions in T1D.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewed intestinal inflammation.","authors":"Yusuke Yamashita, Hideki Kosako, Takashi Kato, Izumi Sasaki, Sadahiro Iwabuchi, Yuri Fukuda-Ohta, Tadashi Okamura, Misato Tane, Shotaro Tabata, Kazutaka Nakashima, Ken Tanaka, Kazunori Shiraishi, Yuki Uchihara, Daisuke Okuzaki, Kyoichi Isono, Atsushi Shibata, Tsunehiro Mizushima, Hiroaki Hemmi, Nobuo Kanazawa, Seiji Kodama, Hiroaki Miyoshi, Koichi Ohshima, Shinichi Hashimoto, Yoshio Fujitani, Takashi Sonoki, Shinobu Tamura, Tsuneyasu Kaisho","doi":"10.1172/jci.insight.199040","DOIUrl":"https://doi.org/10.1172/jci.insight.199040","url":null,"abstract":"<p><p>DNA ligase IV (LIG4) is essential for DNA double-strand break (DSB) repair. Hypomorphic LIG4 variants cause LIG4 syndrome, characterized by growth disturbance, increased radiosensitivity, predisposition to malignancies, adaptive immunodeficiency and inflammatory conditions. Most of these manifestations are recapitulated in hypomorphic LIG4 mutant mice. However, no model mice with defective DSB repair have consistently exhibited inflammation. Here, we have generated mutant mice carrying the LIG4 missense variant, p.W447C, found in a patient with LIG4 syndrome. Lig4W447C/W447C mice showed functional defects of LIGIV and manifested growth retardation, increased radiosensitivity, and life-threatening intestinal inflammation under severe adaptive immunodeficiency. The inflammation was dependent on lymphocytes and characterized by marked infiltration of Th1 cells and macrophages, along with elevated expression of IFN-γ-inducible genes. When Ifng was deleted, Th2 and Th17 instead of Th1 cells drove the inflammation. Single-cell RNA-seq analyses with TCR repertoire revealed that T cells from Lig4W447C/W447C mice preferentially used proximal Vα and Jα segments in V regions of TCRα chains and exhibited expansion of several clonotypes, a substantial portion of which were CD4 T cells expressing IFN-γ. Thus, our hypomorphic Lig4 mutant mice represent a unique model for studying Th1-skewed intestinal inflammation under severe adaptive immunodeficiency.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873942","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}
JCI insightPub Date : 2026-09-01eCollection Date: 2026-10-08DOI: 10.1172/jci.insight.207327
Christina Gkantsinikoudi, Joshua P Dignam, Raju Kumar, Elliot Jokl, Meenakshi Rana, Wenhao Li, Maryna Samus, Stephanie Landi, Varinder S Athwal, Timothy J Kendall, Antal Rot, Jonathan A Fallowfield, Karen Piper Hanley, William Alazawi, Neil P Dufton
{"title":"Mapping vascular plasticity during fibrogenesis identifies fibrosis-associated endothelial cells in early-stage liver disease.","authors":"Christina Gkantsinikoudi, Joshua P Dignam, Raju Kumar, Elliot Jokl, Meenakshi Rana, Wenhao Li, Maryna Samus, Stephanie Landi, Varinder S Athwal, Timothy J Kendall, Antal Rot, Jonathan A Fallowfield, Karen Piper Hanley, William Alazawi, Neil P Dufton","doi":"10.1172/jci.insight.207327","DOIUrl":"10.1172/jci.insight.207327","url":null,"abstract":"<p><p>Vascular plasticity is a crucial biological asset enabling our bodies to rapidly adapt to infections and acute inflammation. However, repeated insults during chronic disease can result in these vascular adaptations becoming irreversible, thereby driving disease progression and fibrosis. This study aimed to understand if phenotypic changes in endothelial cell (EC) identity could be indicative of progressive fibrosis and thereby offer diagnostic and therapeutic opportunities for patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We integrated high-resolution imaging and proteomic and transcriptomic analysis, which collectively highlighted a central role for endothelial-mesenchymal transition-induced (EndMT-induced) EC plasticity in the derivation of fibrosis-associated EC (FAEC). We demonstrated that: (a) full-spectrum flow cytometry can provide new opportunities to categorize and phenotype EC subpopulations; (b) 2 distinct EndMT-derived FAEC subpopulations expanded during fibrogenesis (THY1.2+ICAM1+ and TAGLN+MCAM+ EC) that displayed unique immunomodulatory and metabolic phenotypes; (c) TAGLN+ FAEC are a conserved, profibrotic cell type that arose at early stages of MASLD; and (d) increased hepatic expression of TAGLN was significantly associated with detrimental patient outcomes at all stages of liver disease. This study paves the way for the development of FAEC-specific diagnostic and therapeutic approaches to tackle progressive fibrotic disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873977","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}
JCI insightPub Date : 2026-09-01eCollection Date: 2026-10-08DOI: 10.1172/jci.insight.200728
Yanting Chen, Yu Li, Jiafa Ren, Chia-Chun Wu, Xiaohan Lu, Achintya Inumarty, Steven D Crowley, Jamie R Privratsky
{"title":"The myeloid IL-1 receptor limits IL-27-mediated endothelial type I IFN during nephrotoxic serum nephritis.","authors":"Yanting Chen, Yu Li, Jiafa Ren, Chia-Chun Wu, Xiaohan Lu, Achintya Inumarty, Steven D Crowley, Jamie R Privratsky","doi":"10.1172/jci.insight.200728","DOIUrl":"10.1172/jci.insight.200728","url":null,"abstract":"<p><p>Autoimmune kidney diseases can cause glomerulonephritis and tubulointerstitial nephritis, which if unresolved, lead to progressive glomerulosclerosis and tubulointerstitial fibrosis. The IL-1 receptor (IL-1R1) is known to have divergent and cell-specific effects in kidney injury. We hypothesized that IL-1R1 would dampen pro-inflammatory activation of myeloid cells such that deletion of myeloid cell IL-1R1 would exacerbate autoimmune nephritis. Mice with myeloid cell-specific deletion of IL-1R1 (LysMCre+/Il1r1fl/fl, hereafter MKO) and littermate controls (LysMCre-/Il1r1fl/fl, MWT) were subjected to nephrotoxic serum (NTS) nephritis. MKO mice demonstrated worsened glomerular and tubular injury as indicated by increased albuminuria, glomerular injury scores, and kidney mRNA levels of kidney injury molecule 1 (KIM-1) (Havcr1) and neutrophil gelatinase-associated lipocalin (NGAL/Lcn2). We further found that myeloid IL-1R1 deficiency resulted in increased myeloid cell ER stress and expression of the heterodimeric cytokine Ebi3/Il27a (IL-27). IL-27 then induced increased type I IFN expression by kidney endothelial cells. In turn, anti-IL-27 limited type I IFN expression in endothelial cells and NTS nephritis, and anti-IFNAR1 therapy ameliorated glomerular and tubular injury in MKO mice. Thus, we demonstrated a myeloid cell/endothelial cell immunoregulatory axis whereby myeloid IL-1R1 activity constrained endothelial type I IFN generation to limit chronic kidney damage.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887665","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}
JCI insightPub Date : 2026-08-27eCollection Date: 2026-10-08DOI: 10.1172/jci.insight.194766
Hai Duc Nguyen, Andrew K Ding-Su, Caroline Soulas, Tricia H Burdo, Patrick Autissier, Pasiri Sithinamsuwan, Nitiya Chomchey, Jintanat Ananworanich, Victor Valcour, Silvia Ratto-Kim, Woong-Ki Kim, Kenneth C Williams
{"title":"Monocyte correlates of neurocognitive impairment in chronic HIV infection include early, persistent changes with ART.","authors":"Hai Duc Nguyen, Andrew K Ding-Su, Caroline Soulas, Tricia H Burdo, Patrick Autissier, Pasiri Sithinamsuwan, Nitiya Chomchey, Jintanat Ananworanich, Victor Valcour, Silvia Ratto-Kim, Woong-Ki Kim, Kenneth C Williams","doi":"10.1172/jci.insight.194766","DOIUrl":"10.1172/jci.insight.194766","url":null,"abstract":"<p><p>Persistent monocyte activation contributes to HIV-associated neurocognitive disorders (HAND), yet biomarkers that predict neurocognitive impairment before and after antiretroviral therapy (ART) remain incompletely defined. We evaluated monocyte subsets and activation markers in participants from the SEARCH007 cohort before ART initiation and at 6 and 12 months following treatment. Increased frequencies of CD14+CD16+ monocytes and elevated CD163 expression were associated with worsening neurocognitive performance and HAND severity. Plasma soluble CD163 levels increased with neurocognitive impairment and correlated with plasma HIV RNA levels, while CCR2 expression was associated with a composite neuropsychological performance Z-score (NPZglobal). Notably, CD169 expression was elevated across all monocyte subsets and demonstrated a stepwise increase with worsening neurocognitive impairment. Although ART reduced overall monocyte activation, elevated CD169 expression persisted in some individuals despite virologic suppression. Bayesian kernel machine regression and random forest analyses identified CD169 expression as one of the strongest predictors of cognitive impairment, surpassing plasma viral load, CD4+ T cell count, and several established monocyte activation markers. These findings identify monocyte CD169 expression as a biomarker of neurocognitive dysfunction before and during the first year of ART and support further investigation of its role in HAND pathogenesis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840188","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}
JCI insightPub Date : 2026-08-27eCollection Date: 2026-10-08DOI: 10.1172/jci.insight.202675
Jingjing Tang, Jenny E Kanter, Baohai Shao, Masami Shimizu-Albergine, Farah Kramer, Ah Reum Khang, Jason Luo, Huaqing Zheng, Alan Tran, Jocelyn Cervantes, Jeremy M Frey, Mauricio D Dorfman, Cheng-Chieh Hsu, Laura J den Hartigh, Tomas Vaisar, Brandon Sj Davies, Adam E Mullick, George N Ioannou, Gordon I Smith, Samuel Klein, Nicholas O Davidson, Karin E Bornfeldt
{"title":"Macrophage TREM2 is a triglyceride-rich lipoprotein receptor that undergoes shedding in prediabetic hepatic steatosis.","authors":"Jingjing Tang, Jenny E Kanter, Baohai Shao, Masami Shimizu-Albergine, Farah Kramer, Ah Reum Khang, Jason Luo, Huaqing Zheng, Alan Tran, Jocelyn Cervantes, Jeremy M Frey, Mauricio D Dorfman, Cheng-Chieh Hsu, Laura J den Hartigh, Tomas Vaisar, Brandon Sj Davies, Adam E Mullick, George N Ioannou, Gordon I Smith, Samuel Klein, Nicholas O Davidson, Karin E Bornfeldt","doi":"10.1172/jci.insight.202675","DOIUrl":"10.1172/jci.insight.202675","url":null,"abstract":"<p><p>Prediabetes is associated with increased production of triglyceride-rich lipoproteins (TRLs), cardiovascular disease (CVD), and hepatic steatosis, which is linked to increased plasma levels of soluble TREM2 (sTREM2), the shed domain of TREM2 (triggering receptor expressed on myeloid cells 2). Whether and how TREM2 shedding contributes to elevated TRLs is unknown. By complementary analyses of individuals with prediabetes and hepatic steatosis and preclinical models, we show that plasma sTREM2 levels correlate positively with plasma apolipoprotein C3 (APOC3), an apolipoprotein that slows TRL catabolism and predicts CVD risk. Individuals with prediabetes and hepatic steatosis had higher plasma concentrations of APOC3-rich TRLs 35 to 60 nm in diameter than healthy controls. Mouse models of prediabetes with hepatic steatosis revealed that the increased plasma concentrations of sTREM2, APOC3, and TRLs were due to activation of macrophage ADAM17, a TREM2 sheddase. Preserving macrophage full-length TREM2 protected against the elevated plasma APOC3, sTREM2, dyslipidemia, and atherosclerosis, whereas TREM2 deficiency increased APOC3, TRLs, and atherosclerosis. Mechanistically, full-length TREM2 mediates macrophage TRL uptake, preventing excessive hepatic APOC3-rich TRL release and atherosclerosis. Our findings identify macrophage TREM2 shedding as an upstream contributor to the elevated TRLs in hepatic steatosis, providing a mechanistic link between hepatic steatosis and CVD risk in prediabetes.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840260","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}
JCI insightPub Date : 2026-08-25eCollection Date: 2026-10-08DOI: 10.1172/jci.insight.203285
Jintao Yu, Miguel A Ramirez, Yi-Zhi Wang, Seby Edassery, Maxwell Shramuk, SangEun Yeom, Casey Jiaxi Li, Yuvraj Joshi, Mary Ann Cheatham, Mark A Rutherford, Leah J Welty, Jeffrey N Savas
{"title":"Heat shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss.","authors":"Jintao Yu, Miguel A Ramirez, Yi-Zhi Wang, Seby Edassery, Maxwell Shramuk, SangEun Yeom, Casey Jiaxi Li, Yuvraj Joshi, Mary Ann Cheatham, Mark A Rutherford, Leah J Welty, Jeffrey N Savas","doi":"10.1172/jci.insight.203285","DOIUrl":"10.1172/jci.insight.203285","url":null,"abstract":"<p><p>Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA-seq and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and their supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood-labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin-proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. Together with the existing literature, these findings identify proteotoxic stress in SGNs as a contributor to noise-induced hearing loss and support pharmacological activation of HSF1 as a promising therapeutic strategy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818517","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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