Pub Date : 2026-03-01Epub Date: 2026-02-18DOI: 10.1016/j.trsl.2026.02.008
Qing Zeng , Yuguo Li , Derek Timm , Tyler Johnson , Nickita Mehta , Lukas Martin , Brian Fox , Peter C.M. van Zijl , Glenn A. Walter , Jens T. Rosenberg , Craig W. Vander Kooi , Manuela Corti , Matthew S. Gentry , Ramon C. Sun , Barry J. Byrne , Nirbhay N. Yadav
Pompe disease is a glycogen storage disease caused by the impaired breakdown of glycogen in lysosomes, leading to abnormal glycogen accumulation in tissue. Here we use glycogen nuclear Overhauser effect (glycoNOE) MRI to detect glycogen levels in skeletal muscle in a mouse model of Pompe disease. Moreover, we evaluated if glycoNOE MRI could detect changes in glycogen load after enzyme replacement therapy. The results show that glycoNOE MRI can distinguish between Pompe mice and wildtype controls. Furthermore, the technique detected treatment-dependent changes in muscle glycoNOE signals, which were validated with ex vivo biochemical assays. To demonstrate potential human translation, glycoNOE MRI was applied to two Pompe patients and revealed elevated glycogen levels in patients compared to healthy controls.
{"title":"Mapping glycogen accumulation and treatment effect in Pompe disease with saturation transfer MRI","authors":"Qing Zeng , Yuguo Li , Derek Timm , Tyler Johnson , Nickita Mehta , Lukas Martin , Brian Fox , Peter C.M. van Zijl , Glenn A. Walter , Jens T. Rosenberg , Craig W. Vander Kooi , Manuela Corti , Matthew S. Gentry , Ramon C. Sun , Barry J. Byrne , Nirbhay N. Yadav","doi":"10.1016/j.trsl.2026.02.008","DOIUrl":"10.1016/j.trsl.2026.02.008","url":null,"abstract":"<div><div>Pompe disease is a glycogen storage disease caused by the impaired breakdown of glycogen in lysosomes, leading to abnormal glycogen accumulation in tissue. Here we use glycogen nuclear Overhauser effect (glycoNOE) MRI to detect glycogen levels in skeletal muscle in a mouse model of Pompe disease. Moreover, we evaluated if glycoNOE MRI could detect changes in glycogen load after enzyme replacement therapy. The results show that glycoNOE MRI can distinguish between Pompe mice and wildtype controls. Furthermore, the technique detected treatment-dependent changes in muscle glycoNOE signals, which were validated with <em>ex vivo</em> biochemical assays. To demonstrate potential human translation, glycoNOE MRI was applied to two Pompe patients and revealed elevated glycogen levels in patients compared to healthy controls.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"289 ","pages":"Pages 40-46"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-13DOI: 10.1016/j.trsl.2026.02.006
Sang-Pil Choi , Jun Yang , In-Byung Park , Seok-Jin Kang , Si-Won Park , Chang-Hee Lee , Hyeon Jeong Lee , Joonbeom Bae , Chang-Yong Choi , Jiyoon Shin , Ji-In Kim , Hyun Yong Jin , Young Sik Lee , Taehoon Chun
Colorectal cancer (CRC) remains largely resistant to immune checkpoint inhibitors (ICIs) due to an immunosuppressive tumor microenvironment (TME) shaped by M2-like tumor-associated macrophages (TAMs). Identifying transcriptional regulators of M2-like TAMs in CRC could provide strategies to overcome ICI resistance by reprogramming the TME. In this study, we analyzed single-cell RNA-seq data from CRC patients to identify transcriptional regulators of M2-like TAMs. Notably, MAFB expression was predominantly detected in M2-like TAMs and was significantly higher in mismatch repair-proficient (pMMR) CRC than in mismatch repair-deficient (dMMR) CRC. Moreover, MAFB expression was inversely correlated with relapse-free survival in colon cancer patients. In macrophages, MAFB was induced by the IL-4–STAT6 and IL-10–STAT3 pathways, which drive M2 polarization, and was suppressed by M1-polarizing signals. Myeloid-specific deletion of Mafb, in combination with ICI treatment, reduced colon cancer growth by enhancing anti-tumor immunity through increased activity of M1-like TAMs, which led to increased infiltration of NK cells and activated cytotoxic T cells within the TME. Mechanistically, MAFB acts as a transcriptional activator directly promoting Il4ra, Il10, and Arg1 mRNA expression, supported by the identification of MAF recognition element (MARE) sites within these loci. Consistently, ectopic expression of IL-4 receptor α in Mafb-deficient macrophages restored M2 phenotypes comparable to those of wild-type macrophages. These data highlight the critical cell-intrinsic role of MAFB in regulating M2-like TAMs and provide the first evidence that targeting MAFB enhances ICI efficacy in CRC by reprogramming TAMs toward an anti-tumorigenic M1-like phenotype.
{"title":"Targeting MAFB potentiates immune checkpoint inhibitor efficacy by reprogramming tumor-associated macrophages to an M1-like phenotype in colorectal cancer","authors":"Sang-Pil Choi , Jun Yang , In-Byung Park , Seok-Jin Kang , Si-Won Park , Chang-Hee Lee , Hyeon Jeong Lee , Joonbeom Bae , Chang-Yong Choi , Jiyoon Shin , Ji-In Kim , Hyun Yong Jin , Young Sik Lee , Taehoon Chun","doi":"10.1016/j.trsl.2026.02.006","DOIUrl":"10.1016/j.trsl.2026.02.006","url":null,"abstract":"<div><div>Colorectal cancer (CRC) remains largely resistant to immune checkpoint inhibitors (ICIs) due to an immunosuppressive tumor microenvironment (TME) shaped by M2-like tumor-associated macrophages (TAMs). Identifying transcriptional regulators of M2-like TAMs in CRC could provide strategies to overcome ICI resistance by reprogramming the TME. In this study, we analyzed single-cell RNA-seq data from CRC patients to identify transcriptional regulators of M2-like TAMs. Notably, MAFB expression was predominantly detected in M2-like TAMs and was significantly higher in mismatch repair-proficient (pMMR) CRC than in mismatch repair-deficient (dMMR) CRC. Moreover, MAFB expression was inversely correlated with relapse-free survival in colon cancer patients. In macrophages, MAFB was induced by the IL-4–STAT6 and IL-10–STAT3 pathways, which drive M2 polarization, and was suppressed by M1-polarizing signals. Myeloid-specific deletion of <em>Mafb</em>, in combination with ICI treatment, reduced colon cancer growth by enhancing anti-tumor immunity through increased activity of M1-like TAMs, which led to increased infiltration of NK cells and activated cytotoxic T cells within the TME. Mechanistically, MAFB acts as a transcriptional activator directly promoting <em>Il4ra, Il10</em>, and <em>Arg1</em> mRNA expression, supported by the identification of MAF recognition element (MARE) sites within these loci. Consistently, ectopic expression of IL-4 receptor α in <em>Mafb</em>-deficient macrophages restored M2 phenotypes comparable to those of wild-type macrophages. These data highlight the critical cell-intrinsic role of MAFB in regulating M2-like TAMs and provide the first evidence that targeting MAFB enhances ICI efficacy in CRC by reprogramming TAMs toward an anti-tumorigenic M1-like phenotype.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"289 ","pages":"Pages 27-39"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-14DOI: 10.1016/j.trsl.2026.02.005
Lu Han , Guo-Yuan Lin , Shao-Jie Chen , Qing-Xiu Zhang , Hua-Yue Wu , Tao Huang , Fan Lu , Hong-Fei Pu , Jing-Lin Wang , Tao Ran , Gao-Liang Zou , Jian-Chao Li , Ya Zhang , Xue-Ke Zhao
Liver fibrosis is marked by hepatic stellate cell (HSC) activation and increased glucose consumption. Focal adhesion kinase (FAK) upregulates c-Myc expression in HSCs, promoting aerobic glycolysis. This study explores how FAK promotes HSC activation and glycolysis via TRIM25. Immunohistochemistry (IHC) and Western blotting assessed the expression of FAK, TRIM25, FBXW7, c-Myc, and glycolysis-related proteins in human liver tissues and mouse models. Protein interactions were identified by co-immunoprecipitation (Co-IP) and LC-MS, and FAK and TRIM25 localization was observed by immunofluorescence. FAK inhibition reduced LX-2 cell activation, migration, and glycolysis. Co-IP and immunofluorescence confirmed FAK-TRIM25 interaction. FAK inhibits FBXW7-mediated c-Myc ubiquitination and enhances glycolysis by binding TRIM25’s RING, B-BOX, and SPRY regions. Inhibition of FAK improved liver fibrosis and glycolysis. FAK promotes HSC glycolysis through TRIM25 interaction, and its inhibition mitigates liver fibrosis, suggesting a potential therapeutic target.
{"title":"FAK-TRIM25 promotes HSC activation and glycolysis by inhibiting c-Myc ubiquitination via FBXW7","authors":"Lu Han , Guo-Yuan Lin , Shao-Jie Chen , Qing-Xiu Zhang , Hua-Yue Wu , Tao Huang , Fan Lu , Hong-Fei Pu , Jing-Lin Wang , Tao Ran , Gao-Liang Zou , Jian-Chao Li , Ya Zhang , Xue-Ke Zhao","doi":"10.1016/j.trsl.2026.02.005","DOIUrl":"10.1016/j.trsl.2026.02.005","url":null,"abstract":"<div><div>Liver fibrosis is marked by hepatic stellate cell (HSC) activation and increased glucose consumption. Focal adhesion kinase (FAK) upregulates c-Myc expression in HSCs, promoting aerobic glycolysis. This study explores how FAK promotes HSC activation and glycolysis via TRIM25. Immunohistochemistry (IHC) and Western blotting assessed the expression of FAK, TRIM25, FBXW7, c-Myc, and glycolysis-related proteins in human liver tissues and mouse models. Protein interactions were identified by co-immunoprecipitation (Co-IP) and LC-MS, and FAK and TRIM25 localization was observed by immunofluorescence. FAK inhibition reduced LX-2 cell activation, migration, and glycolysis. Co-IP and immunofluorescence confirmed FAK-TRIM25 interaction. FAK inhibits FBXW7-mediated c-Myc ubiquitination and enhances glycolysis by binding TRIM25’s RING, B-BOX, and SPRY regions. Inhibition of FAK improved liver fibrosis and glycolysis. FAK promotes HSC glycolysis through TRIM25 interaction, and its inhibition mitigates liver fibrosis, suggesting a potential therapeutic target.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"289 ","pages":"Pages 14-26"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146208591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-11DOI: 10.1016/j.trsl.2026.02.004
Xiaoxing Jin , Yuxi Huang , Liyun Luo , Wenyi Tang , Tou Kun Chong , Cunxue Pan , Kan Liu , Jian Chen
Background
Takotsubo syndrome (TTS) is a stress-induced cardiac disorder that closely resembles acute coronary syndrome but lacks effective and safe therapeutic interventions. This study aimed to investigate the cardioprotective effects of transcutaneous auricular vagus nerve stimulation (taVNS), a noninvasive neuromodulation technique, in a rat model of TTS-like cardiomyopathy.
Methods
Sprague–Dawley rats were randomly assigned to three groups: sham, TTS, and TTS + taVNS. TTS was induced by intraperitoneal injection of isoprenaline, while taVNS was applied for 1 hour. Cardiac function was assessed using electrocardiography, heart rate variability, and ventricular electrophysiological recordings. Histopathological changes, inflammatory responses, and autonomic nervous system activity were analyzed. RNA sequencing was performed to explore underlying molecular mechanisms, with key findings validated by RT–qPCR and Western blotting.
Results
Noninvasive taVNS significantly improved left ventricular dysfunction in TTS rats, reducing arrhythmia susceptibility, myocardial injury, and collagen reaction. The treatment significantly suppressed sympathetic overactivation and systemic inflammation. Transcriptomic analysis identified the TLR2/MAPK pathway as a key mediator of inflammation in taVNS-induced protection. Moreover, taVNS significantly downregulated expression of TLR2/MAPK pathway and proinflammatory cytokines confirmed at both mRNA and protein levels compared to the TTS group.
Conclusions
Noninvasive taVNS offers broad cardioprotection in TTS through inhibiting the sympathetic nerve and inflammation. This approach holds promise as an adjunct therapy for TTS, offering benefits in inflammation control, structural preservation, and electrical stability of the heart.
{"title":"Auricular Vagus nerve stimulation alleviates cardiac dysfunction in Takotsubo syndrome by inhibiting excessive activation of the sympathetic nerve system and inflammation","authors":"Xiaoxing Jin , Yuxi Huang , Liyun Luo , Wenyi Tang , Tou Kun Chong , Cunxue Pan , Kan Liu , Jian Chen","doi":"10.1016/j.trsl.2026.02.004","DOIUrl":"10.1016/j.trsl.2026.02.004","url":null,"abstract":"<div><h3>Background</h3><div>Takotsubo syndrome (TTS) is a stress-induced cardiac disorder that closely resembles acute coronary syndrome but lacks effective and safe therapeutic interventions. This study aimed to investigate the cardioprotective effects of transcutaneous auricular vagus nerve stimulation (taVNS), a noninvasive neuromodulation technique, in a rat model of TTS-like cardiomyopathy.</div></div><div><h3>Methods</h3><div>Sprague–Dawley rats were randomly assigned to three groups: sham, TTS, and TTS + taVNS. TTS was induced by intraperitoneal injection of isoprenaline, while taVNS was applied for 1 hour. Cardiac function was assessed using electrocardiography, heart rate variability, and ventricular electrophysiological recordings. Histopathological changes, inflammatory responses, and autonomic nervous system activity were analyzed. RNA sequencing was performed to explore underlying molecular mechanisms, with key findings validated by RT–qPCR and Western blotting.</div></div><div><h3>Results</h3><div>Noninvasive taVNS significantly improved left ventricular dysfunction in TTS rats, reducing arrhythmia susceptibility, myocardial injury, and collagen reaction. The treatment significantly suppressed sympathetic overactivation and systemic inflammation. Transcriptomic analysis identified the TLR2/MAPK pathway as a key mediator of inflammation in taVNS-induced protection. Moreover, taVNS significantly downregulated expression of TLR2/MAPK pathway and proinflammatory cytokines confirmed at both mRNA and protein levels compared to the TTS group.</div></div><div><h3>Conclusions</h3><div>Noninvasive taVNS offers broad cardioprotection in TTS through inhibiting the sympathetic nerve and inflammation. This approach holds promise as an adjunct therapy for TTS, offering benefits in inflammation control, structural preservation, and electrical stability of the heart.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"289 ","pages":"Pages 1-13"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146196359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-22DOI: 10.1016/j.trsl.2026.01.004
Mingjian Piao , Jiayu Xiao , Nan Zhang , Chengjie Li , Jiongyuan Li , Lihua Guan , Shuofeng Li , Zhe Zhu , Shi Feng , Boyu Sun , Dandan Li , Xuzhen Qin , Ling Qiu , Haitao Zhao
Background
Immune checkpoint inhibitors (ICIs) have shown efficacy in hepatobiliary malignancies; however, reliable biomarkers for predicting treatment response remain limited. Peripheral PD-1⁺ T cells, which reflect both T-cell exhaustion and reinvigoration, may serve as novel immune correlates of clinical benefit.
Methods
We prospectively enrolled 99 patients with advanced hepatocellular carcinoma (HCC) or biliary tract cancer (BTC) who received ICIs at Peking Union Medical College Hospital between December 2023 and December 2024. Peripheral blood was collected at baseline and during treatment for flow cytometric quantification of PD-1⁺ T-cell subsets. Patients were randomly divided into a training cohort (n=69) and a validation cohort (n=30). Survival outcomes were analyzed using the Kaplan–Meier method. Baseline predictors were identified by least absolute shrinkage and selection operator (LASSO) regression, followed by nomogram construction.
Results
Responders exhibited significantly longer progression-free survival (PFS; 16.4 vs. 3.5 months, p<0.001) and overall survival (OS; not reached vs. 10.8 months, p<0.001) than non-responders. Higher baseline CD3⁺PD-1⁺ T-cell percentages (32.8% vs. 24.5%, p<0.001) and lower neutrophil-to-lymphocyte ratios (NLR, p=0.002) characterized responders. LASSO regression identified cirrhosis, CD3⁺PD-1⁺ T-cell percentage, and NLR as independent predictors (AUC 0.846 training; 0.670 validation). Longitudinal analysis showed that decreased PD-1⁺ T-cell levels post-treatment correlated with clinical response, while a post-/pre-treatment CD8⁺PD-1⁺ T-cell ratio above 0.07 predicted inferior PFS.
Conclusions
Baseline and dynamic circulating PD-1⁺ T-cell profiles robustly predict ICI response and survival in hepatobiliary cancers, supporting their potential as noninvasive biomarkers for individualized immunotherapy.
{"title":"Peripheral PD-1⁺ T cell signatures predict immunotherapy response and survival in hepatobiliary cancers","authors":"Mingjian Piao , Jiayu Xiao , Nan Zhang , Chengjie Li , Jiongyuan Li , Lihua Guan , Shuofeng Li , Zhe Zhu , Shi Feng , Boyu Sun , Dandan Li , Xuzhen Qin , Ling Qiu , Haitao Zhao","doi":"10.1016/j.trsl.2026.01.004","DOIUrl":"10.1016/j.trsl.2026.01.004","url":null,"abstract":"<div><h3>Background</h3><div>Immune checkpoint inhibitors (ICIs) have shown efficacy in hepatobiliary malignancies; however, reliable biomarkers for predicting treatment response remain limited. Peripheral PD-1⁺ T cells, which reflect both T-cell exhaustion and reinvigoration, may serve as novel immune correlates of clinical benefit.</div></div><div><h3>Methods</h3><div>We prospectively enrolled 99 patients with advanced hepatocellular carcinoma (HCC) or biliary tract cancer (BTC) who received ICIs at Peking Union Medical College Hospital between December 2023 and December 2024. Peripheral blood was collected at baseline and during treatment for flow cytometric quantification of PD-1⁺ T-cell subsets. Patients were randomly divided into a training cohort (n=69) and a validation cohort (n=30). Survival outcomes were analyzed using the Kaplan–Meier method. Baseline predictors were identified by least absolute shrinkage and selection operator (LASSO) regression, followed by nomogram construction.</div></div><div><h3>Results</h3><div>Responders exhibited significantly longer progression-free survival (PFS; 16.4 vs. 3.5 months, p<0.001) and overall survival (OS; not reached vs. 10.8 months, p<0.001) than non-responders. Higher baseline CD3⁺PD-1⁺ T-cell percentages (32.8% vs. 24.5%, p<0.001) and lower neutrophil-to-lymphocyte ratios (NLR, p=0.002) characterized responders. LASSO regression identified cirrhosis, CD3⁺PD-1⁺ T-cell percentage, and NLR as independent predictors (AUC 0.846 training; 0.670 validation). Longitudinal analysis showed that decreased PD-1⁺ T-cell levels post-treatment correlated with clinical response, while a post-/pre-treatment CD8⁺PD-1⁺ T-cell ratio above 0.07 predicted inferior PFS.</div></div><div><h3>Conclusions</h3><div>Baseline and dynamic circulating PD-1⁺ T-cell profiles robustly predict ICI response and survival in hepatobiliary cancers, supporting their potential as noninvasive biomarkers for individualized immunotherapy.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"288 ","pages":"Pages 12-20"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-21DOI: 10.1016/j.trsl.2026.01.003
Yiying Yang , Ke Liu , Muyuan Li , Caiyan Li , Li Wang , Meidong Liu , Hui Luo , Yisha Li , Xiaoxia Zuo , Quanzhen Li , Chuyi Tan , Huali Zhang
Objective
To investigate natural killer (NK) cell dysfunction in anti-MDA5 autoantibody-positive (anti-MDA5⁺) clinically amyopathic dermatomyositis (CADM) patients with rapidly progressive interstitial lung disease (RP-ILD), and explore potential mechanisms related to macrophage activation.
Methods
Differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) from anti-MDA5+ CADM and anti-Jo1-positive (anti-Jo-1+) dermatomyositis patients were profiled using the Illumina HT-12 v4 chip. Cytokine profiles were analyzed using ELISA, and flow cytometry was performed to assess PBMC subsets, NK cell cytotoxicity, and the activation of PLC-γ2 and MAPK signaling. IgG purified from patient serum was used to assess antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) in THP-1/THP-1–like macrophages under poly(I:C) stimulation.
Results
Anti-MDA5⁺ CADM patients exhibited downregulated expression of NK cell activation receptor genes and elevated cytokines such as sCD163 and ferritin compared to anti-Jo-1⁺ patients. NK cell percentages in PBMCs were prominently decreased in anti-MDA5+ patients with RP-ILD compared to those without, and NK cell cytotoxicity or degranulation was weakened, as shown by decreased CD107a and perforin expression, while monocyte populations were increased in RP-ILD patients. IgG purified from anti-MDA5⁺ patient serum impaired NK-cell degranulation in vitro and enhanced ADCC/ADCP activity of THP-1 macrophages following poly(I:C) stimulation. These effects were reduced by CD16 knockdown, indicating involvement of FcγRIII (CD16) dependent interactions. PBMCs from RP-ILD patients exhibited hypophosphorylation of PLCγ2 and ERK, along with hyperphosphorylation of p38, consistent with altered downstream signaling associated with CD16 engagement.
Conclusion
NK-cell dysfunction and enhanced macrophage activation in anti-MDA5⁺ CADM patients with RP-ILD are associated with dysregulated CD16-dependent IgG–cell interactions and perturbations in downstream PLCγ2–MAPK signaling. These findings highlight FcγR-mediated immune dysregulation as a potential contributor to the severe inflammatory phenotype characteristic of RP-ILD, while not establishing antigen-specific mechanisms.
{"title":"IgG from anti-MDA5⁺ CADM patients impairs NK cell function via CD16 in RP-ILD","authors":"Yiying Yang , Ke Liu , Muyuan Li , Caiyan Li , Li Wang , Meidong Liu , Hui Luo , Yisha Li , Xiaoxia Zuo , Quanzhen Li , Chuyi Tan , Huali Zhang","doi":"10.1016/j.trsl.2026.01.003","DOIUrl":"10.1016/j.trsl.2026.01.003","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate natural killer (NK) cell dysfunction in anti-MDA5 autoantibody-positive (anti-MDA5⁺) clinically amyopathic dermatomyositis (CADM) patients with rapidly progressive interstitial lung disease (RP-ILD), and explore potential mechanisms related to macrophage activation.</div></div><div><h3>Methods</h3><div>Differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) from anti-MDA5<sup>+</sup> CADM and anti-Jo1-positive (anti-Jo-1<sup>+</sup>) dermatomyositis patients were profiled using the Illumina HT-12 v4 chip. Cytokine profiles were analyzed using ELISA, and flow cytometry was performed to assess PBMC subsets, NK cell cytotoxicity, and the activation of PLC-γ2 and MAPK signaling. IgG purified from patient serum was used to assess antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) in THP-1/THP-1–like macrophages under poly(I:C) stimulation.</div></div><div><h3>Results</h3><div>Anti-MDA5⁺ CADM patients exhibited downregulated expression of NK cell activation receptor genes and elevated cytokines such as sCD163 and ferritin compared to anti-Jo-1⁺ patients. NK cell percentages in PBMCs were prominently decreased in anti-MDA5<sup>+</sup> patients with RP-ILD compared to those without, and NK cell cytotoxicity or degranulation was weakened, as shown by decreased CD107a and perforin expression, while monocyte populations were increased in RP-ILD patients. IgG purified from anti-MDA5⁺ patient serum impaired NK-cell degranulation <em>in vitro</em> and enhanced ADCC/ADCP activity of THP-1 macrophages following poly(I:C) stimulation. These effects were reduced by CD16 knockdown, indicating involvement of FcγRIII (CD16) dependent interactions. PBMCs from RP-ILD patients exhibited hypophosphorylation of PLCγ2 and ERK, along with hyperphosphorylation of p38, consistent with altered downstream signaling associated with CD16 engagement.</div></div><div><h3>Conclusion</h3><div>NK-cell dysfunction and enhanced macrophage activation in anti-MDA5⁺ CADM patients with RP-ILD are associated with dysregulated CD16-dependent IgG–cell interactions and perturbations in downstream PLCγ2–MAPK signaling. These findings highlight FcγR-mediated immune dysregulation as a potential contributor to the severe inflammatory phenotype characteristic of RP-ILD, while not establishing antigen-specific mechanisms.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"288 ","pages":"Pages 1-11"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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