Inflammation Research[JOURNAL]
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200 papers
IBD risk locus rs1077773 enhances aryl hydrocarbon receptor activity and modulates immune cell function in vitro.
King AC, Seiler K, Swanson K … +2 more , Ciorba MA, Alvarado DM
Inflamm Res · 2026 Apr · PMID 41961102 · Full text
INTRODUCTION: The inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) are disorders that cause chronic inflammation of the gastrointestinal tract. Both genetic and environmental factors con...
INTRODUCTION: The inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) are disorders that cause chronic inflammation of the gastrointestinal tract. Both genetic and environmental factors contribute to the pathogenesis of IBD. There are currently >200 known genetic susceptibility loci for the development of IBD. The physiological impact of the majority of these loci remain a gap in our knowledge. One such locus is the single nucleotide polymorphism rs1077773, located ~56 kbp downstream from the aryl hydrocarbon receptor (AHR) gene. AHR is a ligand-activated transcription factor that is crucial to maintaining intestinal homeostasis. We hypothesized that rs1077773 enhances AHR activity to regulate mucosal immune response and maintain intestinal homeostasis. METHODS: All study procedures and reagents were approved by the Washington University Institutional Review Board (#202011003). Patient biopsies were collected at Barnes Jewish Hospital and genotyped using the IBD Genetics Consortium custom GSA SNP chip (Broad Institute) followed by imputation using TopMed Imputation Server at University of Michigan. Patient derived organoids (PDOs; N=3 G/G, N=4 G/A, N=5 A/A) were derived and maintained in 3D culture and supplemented with 50% L-WRN conditioned medium with passage every 3-4 days as previously described. PDOs were treated with AHR agonist 6-Formylindolo[3,2-b]carbazole (FICZ) or vehicle for 48 h. Expression of AHR and its transcriptional targets Cytochrome P450 1A1 (CYP1A1) and CYP1B1 was assessed by RT-qPCR. Blood was collected from pediatric patients undergoing intestinal resection at St. Louis Children's Hospital and was genotyped with custom TaqMan SNP assay (N=3 G/G, N=5 G/A). Peripheral blood monocyte-derived macrophages (MDMΦs) were treated with lipopolysaccharide in the presence or absence of AHR ligands FICZ or indole-3-carboxaldehyde for 24 h. Cytokine levels in culture supernatant were measured via using the ProcartaPlex human cytokine, chemokine, and growth factor 45-plex (ThermoFisher) on a Luminex FLEXMAP3D instrument. RESULTS: AHR expression was similar across genotypes and treatments. PDOs homozygous for rs1077773 demonstrate enhanced CYP1A1 expression in response to AHR activation. In MDMΦs, cytokine secretion was stimulated by LPS treatment and was abrogated by FICZ treatment. MDMΦs with rs1077773 alternate allele demonstrated significant reduction in secretion of 12 cytokines and chemokines. CONCLUSIONS: This work demonstrates that rs1077773 enhances AHR activity and modulates epithelial and immune cell function in vitro. Further mechanistic understanding of this locus and its correlates could improve our understanding of the molecular mechanisms of IBD susceptibility and may lead to novel personalized therapeutic approaches in IBD.
Protectin DX reduces inflammatory pain initiated by superoxide anion in mice: targeting leukocyte recruitment, oxidative stress, cytokine production and TRPV1 nociceptive sensory neuron activation.
Carneiro JA, Bianchini BHS, Martelossi-Cebinelli G … +12 more , Artero NA, Maximiano TKE, Franciosi A, Dionisio AM, Yaekashi KM, Carvalho TT, da Silva MDV, Rasquel-Oliveira FS, Zanoveli JM, Fattori V, Casagrande R, Verri WA
Inflamm Res · 2026 Apr · PMID 41925851 · Full text
OBJECTIVE AND DESIGN: This study investigated the antinociceptive potential and mechanisms of Protectin DX (PDX) in a KO-induced inflammatory pain. TREATMENT: Male mice received PDX (1, 3, or 10 ng) or vehicle (0.7% etha...
OBJECTIVE AND DESIGN: This study investigated the antinociceptive potential and mechanisms of Protectin DX (PDX) in a KO-induced inflammatory pain. TREATMENT: Male mice received PDX (1, 3, or 10 ng) or vehicle (0.7% ethanol in sterile saline) intraperitoneally (i.p.), 1 h before KO (30 µg intraplantar [i.pl.] or 1 mg [i.p.]). METHODS: Upon KO injection, evoked (mechanical and thermal hyperalgesia, and mechanical allodynia) and non-evoked pain behaviors (weight distribution and overt pain-like behaviors), immune cell recruitment (histopathology and immunofluorescence), cytokine production (ELISA), ROS production (NBT assay), antioxidant capacity (ABTS, FRAP, GSH and catalase assays), TRPV1, and neuronal activation (immunofluorescence and calcium imaging) and toxicity parameters (ALT, AST, urea, creatinine and myeloperoxidase assays) were investigated. Motor performance, mechanical and thermal hyperalgesia were also evaluated without the KO injection. RESULTS: PDX reduced evoked and non-evoked pain, leukocyte recruitment, production of pro-inflammatory cytokines (TNF-α and IL-1β), and oxidative stress. PDX inhibited TRPV1 activity, resulting in inhibition of nociceptive neuron activation. PDX did not alter the plasma levels of ALT, AST, urea, and creatinine, or stomach myeloperoxidase activity. Also, PDX did not affect the basal mechanical and thermal sensitivity and motor activity. CONCLUSION: PDX inhibits superoxide anion-triggered pain and inflammation, through anti-inflammatory, antioxidant, and neuronal component modulation mechanisms.
Multifaceted regulation of immune cells in radiation-induced pulmonary fibrosis: from mechanistic insights to targeted therapies.
Shen L, Zhang W, Yang Y … +7 more , Du Z, Fu S, Huang F, Yang X, Li J, Ran Y, Hao Y
Inflamm Res · 2026 Apr · PMID 41922825 · Publisher ↗
BACKGROUND: Radiation induced pulmonary fibrosis (RIPF) is a life threatening and frequent complication that can occur after radiotherapy to thoracic cancers, and has a complicated pathogenesis and few treatment options....
BACKGROUND: Radiation induced pulmonary fibrosis (RIPF) is a life threatening and frequent complication that can occur after radiotherapy to thoracic cancers, and has a complicated pathogenesis and few treatment options. Recent data suggest that immune cells are the centerpiece of this mechanism, and constitute a complex system of regulation. OBJECTIVE: This review systematically summarizes the dynamic roles and molecular mechanisms of key immune cells in RIPF initiation and progression, and reviews current advances in targeted immunotherapies. METHODS: A comprehensive literature search was conducted in PubMed and Web of Science for studies on immune regulation and therapeutic strategies in RIPF. RESULTS: RIPF exhibits profound spatiotemporal heterogeneity, with immune cell subsets evolving dynamically from inflammation to fibrosis. Macrophages transcend the M1/M2 dichotomy, encompassing specialized subsets. Neutrophils promote fibrosis via NETosis and STAT3/NLRP3 pathways, while eosinophils switch from protective to pathogenic phenotypes. Beyond Th1/Th2 imbalance, Tregs and Th17 cells critically contribute to fibrosis. Emerging targeted strategies-including nanomaterials, natural compounds, and specific inhibitors-have shown promising preclinical results. CONCLUSION: Understanding the spatiotemporally specific functions of immune cells is crucial for developing precision immunotherapies. Future research should focus on biomarker-guided combination strategies to transform RIPF into a preventable and manageable condition.
NPC1L1, stabilized by PABPC1/IGF2BP1, accelerates atherosclerosis by enhancing CYP11A1-mediated mitophagy and ferroptosis.
Zhang G, Song B, Huang X … +1 more , Shi J
Inflamm Res · 2026 Apr · PMID 41917551 · Publisher ↗
In our previous study, we identified Niemann-Pick C1 like intracellular cholesterol transporter 1 (NPC1L1) as a key contributor in lipid oxidative stress during atherosclerosis (AS) progression. However, the regulation m...
In our previous study, we identified Niemann-Pick C1 like intracellular cholesterol transporter 1 (NPC1L1) as a key contributor in lipid oxidative stress during atherosclerosis (AS) progression. However, the regulation mode of its expression and the specific approaches by which it functions in lipid oxidative stress are still unclear. HUVECs and macrophages were treated with oxidized low-density lipoprotein (ox-LDL) to induce endothelial cell injury. First, the effects of the RNA binding proteins IGF2BP1 and poly (A) binding protein cytoplasmic 1 (PABPC1) on the stability of NPC1L1 mRNA was evaluated. The interaction between NPC1L1 and cytochrome P450 family 11 subfamily A member 1 (CYP11A1) was analyzed using Co-IP, and the co-localization of the two was detected using immunofluorescence. Combined with qPCR, Western blotting, CCK8, ferroptosis-related index and mitophagy-related index determination were performed to evaluate the expression of CYP11A1 in ox-LDL-treated HUVECs and its role of ferroptosis and mitophagy. Subsequently, pcDNA-NPC1L1 or CYP11A1 siRNA were individually or altogether transfected into ox-LDL-treated HUVECs to verify the involvement of CYP11A1 in NPC1L1-mediated ferroptosis and mitochondrial oxidative stress. Finally, ApoE-/- mice were fed with high-fat diet to establish an AS model in vivo and sh-NPC1L1 and/or Ad-CYP11A1 were injected via tail vein to verify the therapeutic effect of NPC1L1 knockdown on AS and reversal effect of CYP11A1. Either knockdown of IGF2BP1 or PABPC1 reduced NPC1L1 mRNA stability. Mechanistically, NPC1L1 interacted with CYP11A1 and promoted CYP11A1 protein expression. CYP11A1 was upregulated in ox-LDL-treated HUVECs and overexpression of CYP11A1 induced ferroptosis by activating excessive mitophagy, and knockdown of CYP11A1 reversed the promotion of NPC1L1 on mitophagy and ferroptosis in ox-LDL treated HUVECs. In vivo, injection of the sh-NPC1L1 lentiviral vector inhibited AS progression, while injection of the LV-CYP11A1 lentiviral vector attenuated the protective effect of sh-NPC1L1 on AS. PABPC1 and IGF2BP1 synergistically stabilized NPC1L1 mRNA, and NPC1L1 interacted with CYP11A1 to induce endothelial mitophagy and ferroptosis during AS.
Shenfu Injection reduces septic lethality by preserving glycocalyx integrity and inhibiting caspase-11-dependent pyroptosis.
Zhang C, Chen H, Wang Z … +6 more , Wang X, Li Z, Liang F, Shi J, Lu B, Tang Y
Inflamm Res · 2026 Apr · PMID 41917468 · Publisher ↗
OBJECTIVE AND DESIGN: Sepsis is a life-threatening condition and a leading cause of in-hospital mortality, characterized by dysregulated inflammatory responses. Using murine models, this study investigated whether Shenfu...
OBJECTIVE AND DESIGN: Sepsis is a life-threatening condition and a leading cause of in-hospital mortality, characterized by dysregulated inflammatory responses. Using murine models, this study investigated whether Shenfu Injection (SFI), a clinically approved botanical formulation, protects against sepsis by preserving glycocalyx integrity and modulating noncanonical inflammasome signaling mediated by murine caspase-11. MATERIAL AND SUBJECTS: C57BL/6 mice were subjected to cecal ligation and puncture (CLP) or endotoxemia and treated with SFI or saline. Seven-day survival, organ injury, plasma cytokines, and glycocalyx markers were assessed. For mechanistic studies, knockout mice (Caspase-11, NLRP3, Hpse) and primary peritoneal macrophages were used to evaluate cytosolic LPS delivery, caspase-11-LPS interaction, and gasdermin D (GSDMD) cleavage. RESULTS: SFI treatment significantly improved survival in endotoxemia (15% vs. 54%, P < 0.05) and CLP models (15% vs. 45%, P < 0.05). Treated mice displayed reduced organ injury and lower plasma IL-1α and IL-1β levels. Mechanistically, SFI selectively inhibited caspase-11 activation and GSDMD cleavage, thereby attenuating pyroptosis. Upstream, SFI preserved glycocalyx integrity by preventing heparanase-mediated degradation, which in turn blocked outer membrane vesicle (OMV)-driven cytosolic LPS delivery. CONCLUSIONS: SFI mitigates organ damage and reduces lethality in sepsis by targeting a central pathogenic axis involving glycocalyx degradation, OMV-mediated LPS translocation, and caspase-11-dependent pyroptosis, supporting its potential as an adjunctive therapy for sepsis.
Involvement of the PD-1 pathway in the modulation of immune responses during allergic diseases.
Mohamed AH, Al-Samawi RI, Jamali MC … +8 more , Abdul-Jabbar Ali S, Patel AA, Mustafa AEM, Khairallah AS, Mansuri N, Dutta AK, Sadikan MZ, Mahmoud ZH
Inflamm Res · 2026 Apr · PMID 41917459 · Publisher ↗
BACKGROUND: In recent decades, the prevalence of allergic diseases globally has increased markedly. This underscores the necessity for a deeper understanding of the immunoregulatory networks that govern hypersensitivity...
BACKGROUND: In recent decades, the prevalence of allergic diseases globally has increased markedly. This underscores the necessity for a deeper understanding of the immunoregulatory networks that govern hypersensitivity responses. Controlling the balance between T cell activation, tolerance, and immune-mediated tissue damage through inhibitory signaling mechanisms is a key part of maintaining immune homeostasis. The PD-1/PD-L1 and PD-L2 signaling pathways are very important for this. This checkpoint has been well studied in cancer and chronic infections, but its role in allergic diseases is complex and context-dependent. FINDINGS: PD-L1 and PD-L2 have different effects on the immune system. PD-L1 mostly lowers type 1 immunity and raises type 2 immunity, while PD-L2 mostly promotes type 1 polarization and limits type 2 inflammation. This review goes beyond the well-known asthma model to critically examine new evidence suggesting that the PD-1 pathway may be involved in a wide range of allergic disorders. We integrate recent discoveries from allergic rhinitis, conjunctivitis, dermatological disorders, food allergies, and anaphylaxis, emphasizing how the tissue microenvironment, cellular origin, and disease stage collectively influence whether PD-1 signaling facilitates or inhibits allergic inflammation. By analyzing contradictory findings and identifying gaps in knowledge, we present an advanced model of PD-1 function in allergy. CONCLUSION: We evaluate the therapeutic possibilities and associated risks of targeting this checkpoint for immunomodulation. In recent decades, the prevalence of allergic diseases globally has increased markedly. This underscores the necessity for a deeper understanding of the immunoregulatory networks that govern hypersensitivity responses. Controlling the balance between T cell activation, tolerance, and immune-mediated tissue damage through inhibitory signaling mechanisms is a key part of maintaining immune homeostasis. The PD-1/PD-L1 and PD-L2 signaling pathways are very important for this. This checkpoint has been well studied in cancer and chronic infections, but its role in allergic diseases is complex and context-dependent. PD-L1 and PD-L2 have different effects on the immune system. PD-L1 mostly lowers type 1 immunity and raises type 2 immunity, while PD-L2 mostly promotes type 1 polarization and limits type 2 inflammation. This review goes beyond the well-known asthma model to critically examine new evidence suggesting that the PD-1 pathway may be involved in a wide range of allergic disorders. We integrate recent discoveries from allergic rhinitis, conjunctivitis, dermatological disorders, food allergies, and anaphylaxis, emphasizing how the tissue microenvironment, cellular origin, and disease stage collectively influence whether PD-1 signaling facilitates or inhibits allergic inflammation. By analyzing contradictory findings and identifying gaps in knowledge, we present an advanced model of PD-1 function in allergy and evaluate the therapeutic possibilities and associated risks of targeting this checkpoint for immunomodulation.
What are the key predictors of visual function recovery in uveitis? A systematic review and meta-analysis unraveling structural, genetic, and immunological determinants.
Chen KY, Chan HC, Chan CM
Inflamm Res · 2026 Apr · PMID 41917455 · Publisher ↗
BACKGROUND: Uveitis represents a heterogeneous inflammatory disorder of the uveal tract that remains a major cause of preventable blindness worldwide. Visual recovery following uveitis is highly variable, influenced by c...
BACKGROUND: Uveitis represents a heterogeneous inflammatory disorder of the uveal tract that remains a major cause of preventable blindness worldwide. Visual recovery following uveitis is highly variable, influenced by complex interactions between structural, genetic, inflammatory, and therapeutic factors. Understanding these predictors is crucial for optimizing management and prognosis. OBJECTIVES: To identify and synthesize key predictors of visual function recovery in patients with uveitis-associated vision loss through a systematic review and meta-analysis. METHODS: A comprehensive search of PubMed, Cochrane Library, Scopus, Web of Science, Embase and ScienceDirect was conducted for studies published between January 2000 and August 2025. Eligible randomized controlled trials and cohort studies evaluating clinical, structural, or genetic predictors of visual recovery were included. Data were analyzed using Comprehensive Meta-Analysis software, with effect sizes expressed as standardized mean differences (SMDs) or odds ratios (ORs). Methodological quality was assessed using the Newcastle-Ottawa Scale and ROBINS-I tool. RESULTS: Fourteen studies met inclusion criteria. Meta-analysis demonstrated a significant overall improvement in best-corrected visual acuity (BCVA; SMD = 0.303; p < 0.001). Retinal structural integrity showed a strong association with visual recovery (SMD = 0.652), and the odds of achieving visual acuity 20/200 or better increased significantly (OR = 2.65; p < 0.001). Genetic polymorphisms in CCR2/CCR5 were associated with visual outcomes, although genetic evidence was limited and requires independent validation; preserved retinal architecture and longer treatment duration were consistently associated with better visual recovery. CONCLUSION: Visual function recovery in uveitis depends on structural preservation, inflammation control, and genetic determinants. Early detection and sustained treatment targeting retinal integrity are essential to prevent irreversible vision loss and enhance patient-specific prognostication.
Mitochondrial DNA as a driver of inflammation via the cGAS-STING pathway.
Wen X, Yang F, Zhang L … +1 more , Huang D
Inflamm Res · 2026 Apr · PMID 41917448 · Publisher ↗
BACKGROUND: Mitochondrial DNA (mtDNA), acting as a critical damage associated molecular pattern (DAMP), can translocate into the cytoplasm and directly activate the cGAS-STING signaling pathway. This activation induces t...
BACKGROUND: Mitochondrial DNA (mtDNA), acting as a critical damage associated molecular pattern (DAMP), can translocate into the cytoplasm and directly activate the cGAS-STING signaling pathway. This activation induces the production of type I interferons and senescence associated secretory phenotype (SASP), positioning mtDNA as a key regulator of both inflammation and cellular senescence, namely mtDNA-cGAS-STING signaling axis. MAIN TEXT: Here, we summarize the molecular mechanisms by which cytoplasmic escape of mtDNA and activation of the cGAS-STING pathway trigger a series of downstream cascade reactions. In addition, we discuss the role of the mtDNA-cGAS-STING axis in various inflammation-related pathologies, including ocular diseases, neurodegenerative disorders, pulmonary inflammation, cardiovascular diseases, and oral diseases. CONCLUSIONS: Although interventions targeting the mtDNA-cGAS-STING signaling axis have shown promise in preclinical models, challenges regarding specificity, targeted delivery, and potential side effects remain and require further investigation before clinical translation. A deeper mechanistic understanding of the mtDNA-cGAS-STING axis may provide innovative therapeutic strategies for managing inflammation and aging-associated diseases.
The role of PD-1 and Tim-3 in regulating the suppressive activity of myeloid-derived suppressor cells in axial spondyloarthritis: association with clinical and laboratory parameters.
Tyrinova TV, Sakhno LV, Savkin IV … +13 more , Shevela EJ, Tikhonova MA, Morenkova AY, Ilina NA, Chumasova OA, Shkaruba NS, Fedorova AV, Kurochkina YD, Omelchenko VO, Letyagina EA, Korolev MA, Sizikov AE, Chernykh ER
Inflamm Res · 2026 Apr · PMID 41917446 · Publisher ↗
Monocytic myeloid-derived suppressor cells (M-MDSCs) expand in axial spondyloarthritis (axSpA), although their pathogenetic role and functional state are still unclear. The aim of this study was to investigate checkpoint...
Monocytic myeloid-derived suppressor cells (M-MDSCs) expand in axial spondyloarthritis (axSpA), although their pathogenetic role and functional state are still unclear. The aim of this study was to investigate checkpoint receptors PD-1/Tim-3 expression on M-MDSCs in axSpA, assessing their relationship with clinical disease parameters and M-MDSC suppressor potential. The study included 19 healthy donors and 32 axSpA patients. As markers of the suppressor potential of M-MDSCs, suppressor molecules arginase 1 (Arg-1) and tyrosine kinase Mer (MerTK) were evaluated. M-MDSC count and their expression of PD-1, Tim-3, Arg-1, and MerTK were evaluated using flow cytometry. M-MDSC frequency directly correlated with the level of C-reactive protein, whereas PD-1 expression on M-MDSCs inversely correlated with the erythrocyte sedimentation rate. Thus, high axSpA activity was associated with an increased M-MDSC content with unchanged PD-1 expression, whereas low activity was linked to an increased PD-1 expression without changing M-MDSC frequency. Additionally, the PD-1 M-MDSC count directly correlated with the percentage of MerTK M-MDSCs. Tim-3 showed no correlation with the clinical disease parameters; however, an inverse correlation was observed between Tim-3 and Arg-1 expression in M-MDSCs. In turn, the Arg-1 M-MDSCs count in patients receiving non-steroidal anti-inflammatory drugs and having higher disease activity was reduced, while in the patient group receiving tumor necrosis factor alpha-inhibitors and having lower activity, it was increased. The obtained results may indicate a positive role of PD-1 in preventing inflammation in axSpA, whereas Tim-3 presumably weakens the anti-inflammatory M-MDSC potential in axSpA.
ACT001 alleviates sepsis-induced acute lung injury by downregulating PANoptosis via the JAK2/STAT3 pathway.
Zhang N, Zhang H, Ping J … +3 more , Shen N, Fang T, Fu Q
Inflamm Res · 2026 Apr · PMID 41917427 · Publisher ↗
OBJECTIVE: Sepsis-induced acute respiratory distress syndrome (ARDS) is associated with high mortality and limited therapeutic options. ACT001, a novel derivative with anti-inflammatory properties, has shown potential fo...
OBJECTIVE: Sepsis-induced acute respiratory distress syndrome (ARDS) is associated with high mortality and limited therapeutic options. ACT001, a novel derivative with anti-inflammatory properties, has shown potential for mitigating lung injury; however, its underlying mechanisms remain elusive. This study investigates the protective effects of ACT001 against sepsis-induced acute lung injury (ALI) and explores whether these effects involve the regulation of PANoptosis via the JAK2/STAT3 signaling pathway. METHODS: Using lipopolysaccharide (LPS)-stimulated A549 alveolar epithelial cells and a cecal ligation and puncture (CLP)-induced septic rat model, we evaluated the effects of ACT001. Assessments included CCK-8 viability assays, survival analysis, histopathological examination (H&E staining), and ELISA for inflammatory cytokines (IL-6, TNF-α, IL-1β). Immunofluorescence and Western blotting were performed to detect PANoptosis markers (ZBP1, cleaved caspase-3, p-MLKL, N-GSDMD) and JAK2/STAT3 pathway proteins. The JAK2 inhibitor AG490 was employed to validate the involvement of this pathway. RESULTS: ACT001 significantly improved the viability of LPS-stimulated A549 cells and extended the survival of septic rats. It attenuated alveolar histopathological injury, reduced inflammatory cell infiltration, and decreased plasma cytokine levels. Molecular analyses revealed that ACT001 suppressed the expression of PANoptosis markers (ZBP1, cleaved caspase-3, p-MLKL, N-GSDMD) and inhibited JAK2/STAT3 phosphorylation in both models. Notably, treatment with AG490 reproduced these protective effects, supporting the mechanistic role of the JAK2/STAT3 pathway. CONCLUSION: This study demonstrates that ACT001 mitigates sepsis-induced lung injury, likely by inhibiting PANoptosis through the suppression of the JAK2/STAT3 pathway. These findings provide new insights into the interplay between inflammatory cell death and JAK/STAT signaling, suggesting that ACT001 warrants further investigation as a potential therapeutic agent for sepsis-related ARDS.
IDH1 Mutant Glioma Favors Group 3 Innate Lymphoid Cells and Is Resistant to Immune Checkpoint Expression.
Erdem S, Haliloglu Y, Uslu IN … +6 more , Houran M, Ulutabanca H, Vural A, Erturhan MB, Canatan H, Eken A
Inflamm Res · 2026 Apr · PMID 41917320 · Full text
BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations confer distinct biological properties to gliomas, including the reshaping of the tumor immune microenvironment. While T cell dysfunction in glioblastoma has been ex...
BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations confer distinct biological properties to gliomas, including the reshaping of the tumor immune microenvironment. While T cell dysfunction in glioblastoma has been extensively characterized, the role of innate lymphoid cells (ILCs)-critical regulators of tissue homeostasis and early immune responses- remains poorly understood. METHODS: We investigated how IDH1 mutations and their oncometabolite D-2-hydroxyglutarate (D-2HG) influence ILC subset distribution, immune checkpoint expression, and cytokine production in glioma patients, glioma-conditioned medium (GCM) models, and in vivo mouse experiments. Tumor and peripheral blood samples from 32 glioma patients (WHO 2021 classification, grades II-IV) were analyzed by flow cytometry to assess ILC subsets and immunecheckpoint molecules (PD-1, CTLA-4, KLRG1). Tonsil-derived human ILCs were co-cultured with IDH1-mutant or wild-type glioma cells and their GCM. In vitro, ILCs were exposed to graded concentrations of D-2HG, whereas in vivo studies involved intraperitoneal administration of D-2HG or L-2HG in mice to evaluate ILC distribution across lymphoid and mucosal tissues. RESULTS: IDH1-mutant gliomas exhibited increased ILC3 and decreased ILC1 frequencies in both tumor tissue and peripheral blood. ILC3s in IDH1-mutant tumors expressed higher PD-1, whereas ILC2s showed reduced PD-1 levels. In co-culture assays, IDH1-mutant glioma cells and their GCM suppressed PD-1 and CTLA-4 expression on ILCs while promoting proliferation. Exposure to D-2HG recapitulated these effects in a dose-dependent manner, reducing checkpoint expression and enhancing IFN-γ and TNF-α secretion. In vivo, D-2HG and L-2HG differentially altered ILC subset distribution across mucosal and lymphoid compartments. CONCLUSIONS: IDH1 mutations and their associated oncometabolite D-2HG remodel the innate lymphoid cell landscape in gliomas, driving an ILC3-biased phenotype with reduced checkpoint receptor expression. These findings identify ILCs as key modulators of glioma immunity and suggest that targeting innate immune pathways could complement existing immunotherapeutic approaches.
The epigenetic and epitranscriptomic regulation of Brd4-Mettl3 axis on STING mediated vascular calcification.
Zhao J, Luo X, Wang Z … +11 more , Luo W, Wu S, Ma X, Liu H, Chen Y, Pi S, Zhang J, Zhang J, Liu C, Bi X, Qin Z
Inflamm Res · 2026 Apr · PMID 41917296 · Publisher ↗
AIMS: Vascular calcification (VC) predicts cardiovascular risk in diabetes, chronic kidney disease (CKD) and atherosclerosis patients and is closely linked to the osteogenic transdifferentiation of vascular smooth muscle...
AIMS: Vascular calcification (VC) predicts cardiovascular risk in diabetes, chronic kidney disease (CKD) and atherosclerosis patients and is closely linked to the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Our previous work revealed that cGAS-STING signalling pathway in VSMCs increases CKD-associated atherosclerotic plaque vulnerability and recent studies elucidated the involvement of STING in vascular calcification, but its upstream modulation mechanism remains to be elucidated. METHODS AND RESULTS: DNA damage and robust upregulation of STING occurred in high phosphate (Pi)-stimulated VSMCs, calcified aortic tissues from 1,25(OH)VitD (VitD)-overloaded mice and radial arteries from CKD patients, and these changes were accompanied by the activation of the cGAS‒STING signalling pathway. STING deficiency alleviated vascular calcification in CKD model mice. STING knockdown suppressed calcium deposition and the expression of osteogenic transdifferentiation markers in VSMCs, whereas the overexpression of STING or its agonist 2',3'-cGAMP exacerbated VC. Mechanistically, Brd4 was identified as a critical epigenetic regulator of Pi-induced DNA damage, STING activation and VC. Furthermore, the N6-methyladenosine (m6A) modification of STING mRNA was significantly increased in Pi-stimulated VSMCs, increasing its stability. Brd4 depletion decreased the m6A modification of STING and accelerated its degradation. The m6A modification of STING was mediated by the core methyltransferase Mettl3, whose transcription was regulated by Brd4. Finally, C-176 showed translational potential by effectively suppressing vascular calcification and osteogenesis markers expression in both VitD-overloaded mice and Pi-stimulated VSMCs. CONCLUSIONS: Our study elucidated the interplay between Brd4-mediated epigenetic and Mettl3-dependent epitranscriptomic mechanisms governs STING m6A modification and STING may be a potential therapeutic target for vascular calcification.
LncRNA RP11-510J16.3 exacerbates sepsis-associated encephalopathy by facilitating NLRP3-dependent pyroptosis through miR-1290 sequestering.
Liu X, Xiao Y, Lai Y … +7 more , Ding H, Wen Y, He Z, Chen M, Han Y, Jing Y, Wen M
Inflamm Res · 2026 Apr · PMID 41917230 · Publisher ↗
BACKGROUND: Sepsis-associated encephalopathy (SAE) significantly increases mortality in critically ill patients, with blood-brain barrier (BBB) disruption and pyroptosis-driven neuroinflammation recognized as key pathoge...
BACKGROUND: Sepsis-associated encephalopathy (SAE) significantly increases mortality in critically ill patients, with blood-brain barrier (BBB) disruption and pyroptosis-driven neuroinflammation recognized as key pathogenic drivers. Long non-coding RNAs (lncRNAs) regulate inflammatory processes, yet their role in pyroptosis-associated BBB dysfunction during SAE remains unexplored. METHODS: Using integrated bioinformatics analysis of the GSE135838 dataset, we identified dysregulated lncRNAs in SAE. Human brain microvascular endothelial cells (hBMECs) treated with lipopolysaccharide (LPS) were employed as an in vitro model to mimic SAE-associated BBB injury. Cecal ligation and puncture (CLP) was used to induce SAE in mice as an in vivo model. Mechanisms were investigated via RNA interference, luciferase assays, TEER/permeability measurements, and Neuro-behavioral evaluations. RESULTS: We identified lncRNA RP11-510J16.3 was markedly upregulated in SAE patients and LPS-stimulated hBMECs. Functionally, silencing RP11-510J16.3 significantly attenuated NLRP3 inflammasome activation and pyroptosis, evidenced by reduced levels of p-P65, GSDMD, and IL-1β. It also preserved BBB integrity by restoring zonula occludens-1(ZO-1) expression and TEER values. Mechanistically, RP11-510J16.3 functions as a competing endogenous RNA (ceRNA) by sequestering miR-1290, thereby effectively liberating its repression of NLRP3 translation. This mechanism was demonstrated by cytoplasmic colocalization and direct binding. Furthermore, rescue experiments demonstrated that miR-1290 inhibition reversed the suppression of pyroptosis. In vivo, AAV9-mediated miR-1290 overexpression significantly reduced BBB leakage, as evidenced by decreased Evans Blue extravasation. Furthermore, this treatment suppressed key brain pyroptosis markers. Concomitantly, miR-1290 overexpression improved neurocognitive function, demonstrated by enhanced performance in both open-field and maze tests. CONCLUSIONS: This study identifies a novel lncRNA, RP11-510J16.3, which exacerbates SAE by promoting BBB breakdown through the miR-1290/NLRP3-pyroptosis axis. Therapeutic targeting of this pathway preserves neurovascular integrity, presenting a promising strategy for SAE intervention.
Myeloid-derived suppressor cells in sepsis: drivers of persistent immunosuppression and targets for precision immunotherapy.
Wang X, Huang Q, Zuo Z … +3 more , Wang Z, Zhang L, Qian Z
Inflamm Res · 2026 Apr · PMID 41917194 · Publisher ↗
Sepsis is a leading cause of death and long-term disability worldwide and is now recognized as a condition in which an early hyperinflammatory response rapidly transitions into a dominant and often prolonged immunosuppre...
Sepsis is a leading cause of death and long-term disability worldwide and is now recognized as a condition in which an early hyperinflammatory response rapidly transitions into a dominant and often prolonged immunosuppressive state. Among the cellular drivers of this sepsis-induced immunosuppression, myeloid-derived suppressor cells (MDSCs) have emerged as key regulators linking emergency myelopoiesis, metabolic rewiring, and adaptive immune dysfunction. In this narrative review, we summarize current knowledge on the ontogeny, phenotypic subsets, and core suppressive mechanisms of MDSCs in sepsis, including arginase- and inducible nitric oxide synthase (iNOS)-mediated amino acid depletion, reactive oxygen and nitrogen species, inhibitory checkpoint ligands, and profound metabolic and redox reprogramming. We integrate clinical and experimental data demonstrating that MDSCs expand early in sepsis and often remain elevated for weeks to months, with persistent expansion-particularly of polymorphonuclear subsets-associating with lymphopenia, impaired pathogen clearance, secondary infections, chronic critical illness, and late mortality, especially in older or comorbid patients. We further discuss animal and human models used to dissect MDSC biology, the strengths and limitations of current phenotypic and functional definitions, and the role of MDSCs as biomarkers of disease severity, susceptibility to nosocomial infections, and long-term outcomes. Finally, we review emerging therapeutic strategies that directly or indirectly target MDSCs-such as S100A8/A9 and arginase inhibition, metabolic modulation, differentiation-inducing agents, and combinations with immune checkpoint blockade or γ-chain cytokines-and outline key challenges for translating these concepts into precision immunotherapies. A deeper and more standardized understanding of MDSC heterogeneity and dynamics in sepsis will be essential to safely harness these cells as biomarkers and therapeutic targets to restore antimicrobial defense without precipitating renewed hyperinflammation.
Multi-dimensional plasma proteomic profiling elucidates molecular mechanisms and pathophysiological networks in pediatric severe traumatic brain injury.
Cela E, Tweddell D, Daley M … +3 more , Morello M, Cepinskas G, Fraser DD
Inflamm Res · 2026 Mar · PMID 41896418 · Full text
BACKGROUND: Severe traumatic brain injury (sTBI) is a leading cause of trauma-related mortality and morbidity in pediatric populations. The heterogeneous progression of sTBI presents significant challenges for prognosis...
BACKGROUND: Severe traumatic brain injury (sTBI) is a leading cause of trauma-related mortality and morbidity in pediatric populations. The heterogeneous progression of sTBI presents significant challenges for prognosis and pathophysiological investigation, necessitating advances beyond traditional approaches. This study utilized plasma proteomic profiling to identify sTBI-specific protein alterations and functional pathways correlating with clinical variables in pediatric patients. METHODS: We performed plasma proteomic analysis on 20 matched pairs of pediatric sTBI patients and healthy controls. Proximity extension assays quantified 1,472 proteins. Gene set enrichment analysis identified enriched Reactome pathways and Gene Ontology terms among differentially expressed proteins. Pathway-clinical variable associations were calculated using weighted correlation sums between pathway proteins and clinical variables. Protein-protein interaction networks were analyzed using STRING. RESULTS: Using significance thresholds of FDR-adjusted P < 0.05 and fold change ≥ 4, we identified 65 differentially expressed proteins between sTBI samples and controls. Analysis revealed proteins involved in neuroinflammation and upregulated pathways related to cytokine and receptor/ligand signaling. Altered protein expression indicated structural and functional changes in neurons, glial cells, and vasculature. Upregulated pathways positively correlated with injury severity score, hyperglycemia, and coagulopathy, while negatively correlating with vault skull fractures and acidosis. IL-6 emerged as a central hub in protein-protein interactions, with distinct clusters representing opsonization, TNF family signaling, amidation, neuronal/astrocyte injury, and multifaceted sTBI responses. CONCLUSIONS: These findings identify differentially expressed plasma proteins and enriched signaling pathways associated with clinical features, providing novel insights into pediatric sTBI pathophysiology. The identification of IL-6 as a central hub protein and the correlation of specific pathways with injury severity, metabolic dysfunction, and coagulopathy suggest potential targets for therapeutic intervention and prognostic biomarker development. This proteomic approach advances our understanding of the complex molecular cascades underlying pediatric sTBI and may inform precision medicine strategies for improved patient outcomes.
Keratinocytes: pleiotropic orchestrators of cutaneous immunity and Inflammation - Emerging therapeutic paradigms in dermatological pathologies.
Wan L, Zhou Z, Chen Q … +2 more , Jing J, Xu G
Inflamm Res · 2026 Mar · PMID 41896409 · Publisher ↗
BACKGROUND: Keratinocytes, the principal cellular constituents of the epidermis, have transcended their conventional barrier function to emerge as master regulators of cutaneous immune homeostasis and inflammatory pathog...
BACKGROUND: Keratinocytes, the principal cellular constituents of the epidermis, have transcended their conventional barrier function to emerge as master regulators of cutaneous immune homeostasis and inflammatory pathogenesis. In inflammatory skin diseases such as psoriasis, atopic dermatitis, and systemic lupus erythematosus, keratinocytes orchestrate complex inflammatory cascades through intricate signaling networks. MATERIAL AND METHODS: We conducted a comprehensive literature search in the PubMed database. The search was performed using the following key terms: "Keratinocytes", "Inflammation", "Skin immune diseases", "Immune cell", "Glucocorticoids", "Inflammasomes", "Antioxidants", "Neuropeptide" and "Single-Cell Technologies". CONCLUSION: In this review, we summarize that keratinocytes play a pivotal role in inflammatory skin pathologies by engaging in bidirectional communication with T lymphocyte subsets, establishing self-amplifying cytokine circuits (e.g., the HMGB1-mediated loop in SLE and the IL-23/Th17 axis in psoriasis), and constitutively producing local glucocorticoid metabolites. Their immunoregulatory capacity is executed through pattern recognition receptor activation and the maintenance of redox balance via antioxidant defense systems such as the SOD2/Nrf2/ARE pathway. Keratinocytes can produce and secrete inflammasomes and neuropeptides, thereby participating in the regulation of inflammation, pruritus, pain and neuro‑immune crosstalk. Furthermore, cutting-edge single-cell transcriptomic profiling has revealed unprecedented keratinocyte heterogeneity and disease-specific subpopulations. In summary, keratinocyte-targeted strategies offer promising interventions to break pathogenic cycles and restore epidermal barrier function.
Proteomic profiling and pathway analyses reveal molecular signatures and immune networks in pediatric sepsis.
Stranges V, Van Nynatten LR, Tweddell D … +6 more , Cela E, Morello M, Daley M, O'Gorman DB, Cepinskas G, Fraser DD
Inflamm Res · 2026 Mar · PMID 41896381 · Full text
BACKGROUND: Sepsis remains a leading cause of childhood mortality worldwide. Most deaths occur within the first few days of presentation, underscoring the urgent need for early recognition and biologically informed treat...
BACKGROUND: Sepsis remains a leading cause of childhood mortality worldwide. Most deaths occur within the first few days of presentation, underscoring the urgent need for early recognition and biologically informed treatment strategies. The heterogeneous etiology of sepsis involves complex, intertwined biological networks, explaining why single-biomarker approaches have proven inadequate for capturing this complexity. We used high-throughput proximity extension assay technology to comprehensively profile plasma proteins in critically ill pediatric sepsis patients, aiming to identify dysregulated biological pathways that could inform risk stratification and therapeutic development. METHODS: Study participants were prospectively enrolled based on established pediatric sepsis criteria. Plasma proteins were quantified using the Olink proximity extension assay, with differential expression, machine learning, and pathway enrichment analyses performed to define molecular signatures of pediatric sepsis. RESULTS: Analysis of plasma samples from 17 pediatric sepsis patients and 17 age- and sex-matched healthy controls revealed 626 significantly differentially expressed proteins: 399 upregulated and 227 downregulated. The most significantly elevated proteins included calcitonin-related polypeptide α (CALCA), tumor necrosis factor superfamily member 14 (TNFSF14), and asialoglycoprotein receptor 1 (ASGR1). Machine learning identified a minimal 9-protein signature accounting for 90% of discriminatory power between groups. Pathway enrichment analysis revealed profound dysregulation of immune and inflammatory networks. Interleukin-10 (IL-10) signaling emerged as the most significantly enriched pathway, alongside extracellular matrix degradation, IL-4 and IL-13 signaling, and other cytokine signaling pathways. Dysregulated pathways were associated with clinical variables, particularly gram-negative infections and respiratory infection sources. CONCLUSIONS: Pediatric sepsis is characterized by dysregulation of multiple immune and inflammatory pathways rather than isolated protein abnormalities. IL-10 and related cytokine signaling emerged as central nodes, providing insights into the balance between hyperinflammation and immunosuppression in critically ill children. Associations between pathways and clinical variables suggest that specific pathogen types and infection sources trigger distinct patterns of biological network activation, offering potential targets for patient stratification and pathway-directed therapeutics.
Macrophage β-catenin-Ihh axis induces hepatic stellate cell activation and fibrosis in metabolic dysfunction-associated steatohepatitis.
Zhang R, Yang Y, Xiao F … +7 more , He Y, Chai Y, Qiu J, Zhu Q, Sun W, Chen M, Xu Z
Inflamm Res · 2026 Mar · PMID 41896378 · Full text
BACKGROUND & AIMS: Currently, there are no approaches to specifically target macrophage-hepatic stellate cell (HSC) crosstalk in metabolic dysfunction-associated steatohepatitis (MASH). Although the β-catenin signaling p...
BACKGROUND & AIMS: Currently, there are no approaches to specifically target macrophage-hepatic stellate cell (HSC) crosstalk in metabolic dysfunction-associated steatohepatitis (MASH). Although the β-catenin signaling pathway has been implicated in fibrotic diseases, the role and downstream mechanism of macrophage β-catenin in MASH-associated hepatic fibrosis remains incompletely understood. METHODS: Myeloid-specific β-catenin deficiency (β-catenin) mice and the floxed β-catenin (β-catenin) mice were subjected to high-fat diet (HFD) feeding for 28 weeks. We delivered indian hedgehog (Ihh) plasmid in vivo using polyethylenimine nanoparticles, in vivo jetPEI-Man, that specifically deliver to macrophages. RESULTS: Although increased β-catenin activation was observed in the fibrotic liver macrophages of mice after HFD feeding, myeloid-specific β-catenin deficiency protected the liver against HFD-induced steatosis and fibrosis. Furthermore, we found that myeloid-specific β-catenin deficiency suppressed Ihh expression in liver macrophages. In vivo jetPEI-Man-mediated Ihh restoration prevented the improvement in MASH-induced fibrosis that we observed in β-catenin mice. In vitro co-culture experiments indicated that β-catenin activation in macrophages induced Ihh expression and secretion, which then promoted the activation of HSCs. CONCLUSION: Our findings identify the macrophage β-catenin-Ihh axis as a key regulator for controlling hepatic steatosis and fibrosis during MASH.
TET1 deficiency amplifies macrophage inflammatory signaling associated with Crohn's disease.
Perez RK, Paul R, Kumar P … +12 more , Tutkun A, Webb D, McGorty S, Wieckowski T, Yap YS, Leesang TE, Vlantis PI, Telonis AG, Hajdin C, King J, Nabozny G, Cimmino L
Inflamm Res · 2026 Mar · PMID 41896302 · Full text
OBJECTIVE AND DESIGN: To define the role of Ten-Eleven Translocation (TET) proteins in Crohn's disease (CD)-associated inflammation through integrative human and mechanistic studies. MATERIAL: Publicly available CD trans...
OBJECTIVE AND DESIGN: To define the role of Ten-Eleven Translocation (TET) proteins in Crohn's disease (CD)-associated inflammation through integrative human and mechanistic studies. MATERIAL: Publicly available CD transcriptomic and DNA methylation datasets, and primary mononuclear cells and ileal biopsies were analyzed for TET gene expression and signatures. TET1 and TET2 CRISPR/Cas9 knockout macrophage cell lines were generated. TREATMENT: Macrophages were stimulated with LPS in the presence or absence of kinase inhibitors. Conditioned media from macrophages were applied to primary human neutrophils. PBMCs from CD patients and healthy donors were stimulated with LPS for validation. METHODS: Macrophages or primary patients samples were analyzed by high-throughput surface marker profiling, RNA sequencing, 5hmC sequencing, assays of effector function, qRT-PCR, phosphoflow, and cytokine/chemokine release by ELISA. RESULTS: TET1 was the most downregulated TET enzyme in CD blood and ileal tissues, correlating with reduced TET-associated gene signatures and elevated inflammatory mediators. TET1-deficient macrophages exhibited distinct surface phenotypes, reduced PTEN expression, altered 5hmC distribution, and heightened IFN gene expression, ERK activation, and chemokine release associated with enhanced neutrophil migration. PBMCs from CD patients mirrored reduced TET1 expression and exaggerated inflammatory responses. CONCLUSIONS: TET1 functions as a non-redundant regulator of inflammatory macrophages and aberrant chemokine signaling linked to immune cell recruitment in Crohn's disease.
Repetitive transcranial magnetic stimulation modulates neuroinflammation and cell apoptosis via the interaction between Ifit3 and Stat1 for the treatment of neuropathic pain.
Huang M, Xing F, Xu Z … +10 more , Tang H, Zhao L, Yang Y, Deng Q, Shi R, Li L, Zhu J, Chen X, Li D, Wang J
Inflamm Res · 2026 Mar · PMID 41865234 · Publisher ↗
OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS), a non-invasive electrophysiological technique employed in the treatment of neuropathic pain (NeuP), still has an elusive therapeutic mechanism. METHODS: In...
OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS), a non-invasive electrophysiological technique employed in the treatment of neuropathic pain (NeuP), still has an elusive therapeutic mechanism. METHODS: In this study, transcriptomic and proteomic analyses were carried out on the brain tissues of rats with chronic constriction injury (CCI) models. Particular emphasis was placed on the key regulatory molecule Ifit3 and its interacting protein Stat1. RESULTS: Findings revealed that rTMS was capable of significantly ameliorating the elevated expression levels of Ifit3 and Stat1 in the brain tissues of NeuP rats. Moreover, in in-vitro experiments, rTMS effectively mitigated the neuroinflammatory response and the degree of microglial apoptosis. Further investigations demonstrated that overexpressing Ifit3 led to an exacerbation of the aforementioned inflammation and apoptosis related manifestations. Conversely, silencing Ifit3 had a mitigating effect. Additionally, a high degree of consistency was observed in the expression changes of Stat1 and Ifit3. CONCLUSIONS: Collectively, these research outcomes indicate that rTMS exerts its therapeutic effect on NeuP by modulating the inflammatory response and cell apoptosis. During this process, the interaction between Ifit3 and Stat1 assumes a pivotal regulatory role.
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