Journal Of Inflammation (London, England)[JOURNAL]
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200 papers
Montelukast suppresses NLRP3 inflammasome activation as a potential prophylactic agent against gout arthritis flares.
Shippy DC, Evered AH, Ulland TK
J Inflamm (Lond) · 2026 Feb · PMID 41680878 · Full text
BACKGROUND: Gout arthritis (GA) flares are unexpected bouts of heat, swelling, and redness resulting in excruciating pain caused by monosodium urate (MSU) crystal deposition in the synovial joints. GA flare symptoms occu...
BACKGROUND: Gout arthritis (GA) flares are unexpected bouts of heat, swelling, and redness resulting in excruciating pain caused by monosodium urate (MSU) crystal deposition in the synovial joints. GA flare symptoms occur as a by-product of the inflammatory response as immune cells engulf MSU crystals in the joint. The NLRP3 inflammasome is the major source of the inflammatory response to MSU crystals; therefore, we hypothesize that prophylactic administration of agents that target the NLRP3 inflammasome could be used to suppress GA flares. RESULTS: We previously performed a screen of 875 FDA-approved drugs to identify candidates that suppressed NLRP3 inflammasome activation without causing cytotoxicity in bone marrow-derived macrophages (BMDM). In this study, one of the candidates, montelukast, an anti-asthma drug, significantly suppressed Nlrp3- and Caspase-1-dependent IL-1β and IL-18 secretion by BMDM. Furthermore, in an MSU-induced mouse model of GA flares, treatment with montelukast mitigated pro-inflammatory cytokine/chemokine secretion, including inflammasome-dependent cytokines (IL-1β and IL-18), and edema. CONCLUSIONS: Overall, these data suggest montelukast is a robust suppressor of the NLRP3 inflammasome that could be repurposed as a prophylactic agent to mitigate GA flares.
Bromodomain-containing protein 4 in inflammatory diseases: molecular mechanisms and therapeutic potential.
Frascatani R, Marafini I, Colella M … +1 more , Monteleone G
J Inflamm (Lond) · 2026 Feb · PMID 41664183 · Full text
Bromodomain-containing protein 4 (BRD4), a key member of the bromodomain and extra-terminal (BET) family, plays a critical role in regulating gene expression as an epigenetic reader. While its canonical role involves tra...
Bromodomain-containing protein 4 (BRD4), a key member of the bromodomain and extra-terminal (BET) family, plays a critical role in regulating gene expression as an epigenetic reader. While its canonical role involves transcriptional control, BRD4 also acts as a dynamic integrator of intracellular signaling pathways and chromatin architecture, linking environmental and inflammatory stimuli to lasting gene expression changes. Recent research highlights BRD4 as a central regulator in inflammatory transcriptional networks, contributing to chronic inflammation in autoimmune diseases, cardiovascular conditions, metabolic disorders, and cancer-related inflammation. BRD4 interacts with major inflammatory transcription factors, such as NF-κB, STATs, and AP-1, amplifying transcriptional responses and maintaining an open chromatin state at super-enhancers that control inflammatory gene clusters. This has prompted interest in pharmacological strategies targeting BET proteins, with promising anti-inflammatory and antifibrotic effects in preclinical models. This review consolidates current knowledge on BRD4’s molecular mechanisms in inflammation and evaluates the potential of BET inhibitors as therapeutic agents.
Diagnostic and prognostic value of LINC00278 in patients with severe pneumonia and its regulatory role.
Liu Y, Zhou C, Guo Z … +1 more , Liu X
J Inflamm (Lond) · 2026 Jan · PMID 41618373 · Full text
BACKGROUND: To investigate the diagnostic and prognostic value and regulatory role of LINC00278 in severe pneumonia. METHODS: A total of 312 volunteers were enrolled with a follow-up period of 90 days. Blood and bronchoa...
BACKGROUND: To investigate the diagnostic and prognostic value and regulatory role of LINC00278 in severe pneumonia. METHODS: A total of 312 volunteers were enrolled with a follow-up period of 90 days. Blood and bronchoalveolar lavage fluid samples from participants were stored at −80 °C. ROC curves, KM curves, and multivariate Cox regression analyses assessed LINC00278‘s diagnostic and prognostic utility. RT-qPCR examined gene expression; CCK-8 assays evaluated cell proliferation. ELISA measured inflammatory cytokine expression, while commercially available kits quantified oxidative stress levels. DLR and RIP validated gene-target relationships. RESULTS: LINC00278 was upregulated in both blood and bronchoalveolar lavage fluid samples from patients with severe pneumonia. Elevated LINC00278 expression predicted poorer patient outcomes. LPS treatment promoted LINC00278 expression in pulmonary epithelial cells, slowed cell proliferation, and increased inflammatory and oxidative stress levels. miR-149-5p was downregulated in critically ill patients and identified as a target gene of LINC00278. The miR inhibitor reversed the cellular functions and inflammatory levels modulated by si-LINC00278. Forty-nine genes were identified as potential downstream targets of the LINC00278/miR-149-5p pathway. CONCLUSIONS: LINC00278 impairs pulmonary epithelial cell proliferation by suppressing miR-149-5p, elevating cellular inflammation and oxidative stress levels, thereby contributing to poor prognosis in critically ill pneumonia patients. CLINICAL TRIAL NUMBER: Not applicable.
Sepsis induces long-term reprogramming of human HSPCs and drives myeloid dysregulation in sepsis survivors.
De Zuani M, Lázničková P, Hortová Kohoutková M … +15 more , Bosáková V, Andrejčinová I, Vadovičová N, Tomášková V, Mýtniková A, Štíchová J, Tomáš T, Hrdý J, Boráková K, Uldrijan S, Vlková M, Šrámek V, Helán M, Bendíčková K, Frič J
J Inflamm (Lond) · 2026 Jan · PMID 41593458 · Full text
BACKGROUND: Sepsis is a life-threatening condition characterised by an overwhelming immune response and high fatality. While most research has focused on its acute phase, many sepsis survivors remain immunologically weak...
BACKGROUND: Sepsis is a life-threatening condition characterised by an overwhelming immune response and high fatality. While most research has focused on its acute phase, many sepsis survivors remain immunologically weakened leaving them susceptible to serious complications from even mild infections. The mechanisms underlying this prolonged immune dysregulation remain unclear, limiting effective interventions. Here, we analysed whether sepsis induced long-term "training" in hematopoietic stem and progenitor cells (HSPCs), imprinting changes that persist in their myeloid progeny. RESULTS: Peripheral blood analysis of 8 sepsis survivors, 12 patients with septic shock, and 10 healthy donors revealed a significant expansion of CD38 + progenitors in survivors, with increased megakaryocyte-erythroid progenitors and a near significant reduction in mature neutrophil counts. This shift suggests impaired granulopoiesis, favouring immature, immunosuppressive granulocytes. Differentiated macrophages from survivors' HSPCs exhibited impaired metabolic pathways after lipopolysaccharide stimulation, with downregulation of tricarboxylic acid cycle and glycolysis genes, indicating altered immune metabolism. Pathway analysis revealed enhanced type-I interferon (IFN) and JAK-STAT signalling in survivors' macrophages, reflective of potentially tolerance-prone reprogramming. Finally, exposing healthy donor HSPCs to IFNβ during macrophage differentiation reduced HSPC proliferation, increased apoptosis, and induced a metabolic shift towards glycolysis over mitochondrial respiration. CONCLUSIONS: Together, these findings suggest that sepsis induces lasting reprogramming in HSPCs leading to myeloid progeny with altered immune memory that might drive immune dysregulation in survivors. These data open avenues to explore potential targets to better manage long-term immune alterations in sepsis survivors.
Bradykinin reduces wound healing in human umbilical vein endothelial cells via downregulation of vascular endothelial growth factor A.
Dimitrova N, Gierke A, Möhrle R … +6 more , Nemeth J, Brunner C, Hoffmann TK, Greve J, Hahn J, Lochbaum R
J Inflamm (Lond) · 2026 Jan · PMID 41519751 · Full text
INTRODUCTION: Hereditary angioedema (HAE) is characterized by acute swelling attacks triggered by abnormally elevated levels of bradykinin. Despite persistently high bradykinin levels, patients experience only intermitte...
INTRODUCTION: Hereditary angioedema (HAE) is characterized by acute swelling attacks triggered by abnormally elevated levels of bradykinin. Despite persistently high bradykinin levels, patients experience only intermittent swelling episodes. Many HAE patients, however, report triggers such as trauma preceding angioedema attacks. This suggests the involvement of additional factors, such as mechanical damage to the endothelium. Bradykinin-mediated impairment of wound healing may contribute to swelling development—a concept known as the “second hit” hypothesis. Vascular endothelial growth factors (VEGF) and their receptors play a critical role in endothelial wound healing and have also been implicated in bradykinin-mediated angioedema. This study investigates the influence of bradykinin on endothelial wound healing, with a particular focus on VEGF. MATERIALS AND METHODS: Human umbilical vein endothelial cells were incubated with bradykinin and VEGF. Gene and protein expression were analyzed by real-time polymerase chain reaction, western blotting, and immunocytochemistry. Barrier function was assessed by measuring transendothelial electrical resistance, as well as apparent and water permeability. Proliferation rates were determined using resazurin assays and real-time cell analysis. Cell migration was assessed using invasion and migration assays, and the combined effects were evaluated using scratch assays. RESULTS: Bradykinin treatment led to reduced expression of the VEGFA isoform and its receptor VEGFR-2. VEGFA alone had no effect on bradykinin-induced barrier disruption. However, bradykinin significantly decreased endothelial proliferation and migration, resulting in impaired wound healing. This effect was counteracted by the addition of VEGFA. CONCLUSIONS: VEGFA and its receptor VEGFR-2 are key regulators of endothelial wound healing. Bradykinin impairs wound healing by reducing proliferation and migration, likely through downregulation of VEGFA and VEGFR-2. These findings support the hypothesis that bradykinin-mediated impairment of wound healing may contribute to the episodic nature of swelling attacks in patients with bradykinin-mediated angioedema, in line with the second hit hypothesis.
USP8 inhibits cigarette smoke extract combined with LPS-induced inflammatory response and ER stress by regulating the ABCB1-mediated MAPK signaling pathway in human bronchial epithelial cells.
Wang M, Song W, Liu X … +1 more , Meng A
J Inflamm (Lond) · 2025 Dec · PMID 41462251 · Full text
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a significant global cause of morbidity and mortality and is characterized by airway remodeling, inflammation, and endoplasmic reticulum stress (ER stress) prog...
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a significant global cause of morbidity and mortality and is characterized by airway remodeling, inflammation, and endoplasmic reticulum stress (ER stress) progression. Cigarette smoke (CS) is the major risk factor for the occurrence and development of COPD. P-glycoprotein (ABCB1, also known as MDR1) is one of the suggested respiratory tract protection components, found in various tissues with a barrier function, containing tracheobronchial epithelium and lung parenchyma. This study is designed to explore the role and mechanism of ABCB1 in lipopolysaccharide (LPS)/CS extract (CSE)-induced COPD pathological process. METHODS: LPS combined with CSE treatment was used to induce human normal bronchial epithelium (HBE) to construct a COPD cell model. Meanwhile, LPS combined with CSE exposure was utilized to build a COPD mouse model. ABCB1, Ubiquitin-specific peptidase 8 (USP8), and ER stress markers (GRP78 and CHOP), p-p38, p38, p-ERK, and ERK protein levels were determined using western blot. Cell viability and apoptosis were assessed using the Cell Counting Kit-8 (CCK-8) and flow cytometry. Tumor necrosis factor α (TNF-α) and Interleukin-1β (IL-1β) levels were analyzed using ELISA. Apoptosis index of lung tissue in the COPD mouse model was detected using TUNEL assay. After ubibrowser database analysis, the interaction between USP8 and ABCB1 was verified using Co-immunoprecipitation (CoIP) assay. RESULTS: ABCB1 and USP8 expression levels were decreased in LPS combined with CSE-treated HBE cells. ABCB1 and GRP78 were also increased in the COPD mouse model. ABCB1 overexpression could relieve LPS combined with CSE-induced HBE cell inflammatory response and ER stress, as well as LPS and CSE-triggered lung injury in the COPD mouse model. Mechanistically, USP8 triggered the deubiquitination of ABCB1 and prevented its degradation. Furthermore, the phosphorylation of ERK and p38 in LPS combined with CSE-treated HBE cells was enhanced respectively, which manifested that MAPK signaling pathways were activated. USP8 upregulation attenuated LPS combined with CSE-activated MAPK pathways through regulating ABCB1. CONCLUSION: Overexpressing USP8 mitigated LPS combined with CSE-induced inflammatory damage in HBE cells through targeting ABCB1-mediated MAPK signaling, providing a possible therapeutic target for COPD treatment.
Immunomodulatory effects of Purion processed human amniotic membrane allografts in vitro.
Moreno SE, Mikulin J, Massee M … +3 more , Lang J, Olender T, Harper JR
J Inflamm (Lond) · 2025 Dec · PMID 41402824 · Full text
BACKGROUND: The immune system plays a pivotal role in progressing an injury through the healing cascade. However, comorbidities often lead to dysregulation of this response and are implicated in wound chronicity or stall...
BACKGROUND: The immune system plays a pivotal role in progressing an injury through the healing cascade. However, comorbidities often lead to dysregulation of this response and are implicated in wound chronicity or stalling in the inflammatory phase, necessitating clinical intervention. The maternal-fetal interface, one of the most striking immunomodulatory microenvironments to be found in mammals, may be leveraged therapeutically in wound healing through the application of amniotic tissue allografts. METHODS: This study investigates the influence of dehydrated human amnion chorion membrane (DHACM) and lyophilized human amnion and chorion membrane (LHACM) on the inflammatory response of monocytes and macrophages in vitro. Human THP-1 monocytes and macrophages were challenged with lipopolysaccharide (LPS) or LPS + interferon gamma (INFγ), respectively, to model inflammatory conditions. RESULTS: LHACM and DHACM treatment significantly dampened inflammasome activity and pro-inflammatory protein production while enhancing cell survival in LPS-challenged monocytes. LPS/INFγ-challenged macrophages exhibited a phenotypic shift with treatment, synonymous with repair or regeneration functionality. This was further confirmed when these cells demonstrated corresponding attenuation of pro-inflammatory cytokine production, dampened inflammasome activity, and increased survival. Additionally, the rate of efferocytosis by DHACM and LHACM-treated macrophages was substantially elevated, indicating more efficient clearance of dead cell debris. CONCLUSION: These results indicate that DHACM and LHACM modulate the pro-inflammatory response of monocytes and macrophages, while enhancing the pro-reparative functions including efferocytotic capacity and cell survival. These data are suggestive of a potential cellular mechanism by which DHACM and LHACM may facilitate an efficient and appropriate inflammatory response to support the progression through the healing cascade.
Erianin regulates allergic rhinitis via KAT2A-mediated histone succinylation.
Wang HY, Wang CY, Bao QF … +1 more , Chen MF
J Inflamm (Lond) · 2025 Dec · PMID 41387864 · Full text
BACKGROUND: Allergic rhinitis arthritis (AR) is a common chronic inflammatory disease, which may lead to other systemic chronic diseases. Erianin, a natural product isolated from Dendrobium chrysotoxum, has been reported...
BACKGROUND: Allergic rhinitis arthritis (AR) is a common chronic inflammatory disease, which may lead to other systemic chronic diseases. Erianin, a natural product isolated from Dendrobium chrysotoxum, has been reported to exert effects on a variety of diseases. In this work, we aimed to explore the effects and mechanisms of erianin in allergic rhinitis. METHODS: Interleukin-13 (IL-13) was selected to treat nasal epithelial cells (NECs) to establish an in vitro AR model; Ovalbumin (OVA) was used to treat the nasal cavity of mice to establish an in vivo AR model; Cell counting kit 8 (CCK-8) was used to detect the cell activity of nasal epithelial cells after different treatments; Apoptosis and inflammatory cell infiltration of nasal tissue were analyzed by TUNEL and H&E staining, respectively; Mice noses scratching were counted to determine the severity of inflammation; Inflammation-related cytokine expression was examined by qPCR and ELISA to determine how erianin alleviates inflammation; Changes in apoptosis and histone acetylation succinylation modification were examined by Western blotting; Enrichment of KAT2A and histone succinylation at the p65 promoter was detected by ChIP-seq. RESULTS: Erianin inhibited IL-13-induced inflammation in nasal epithelial cells in vitro, while alleviating OVA-induced rhinitis in mice in vivo. In further mechanistic studies, Erianin was found to regulate the disease through KAT2A-mediated histone succinylation. Erianin blocked KAT2A as well as H3K79 succinylation and further inhibited p65 expression, thereby controlling the further development of allergic rhinitis. CONCLUSION: Erianin alleviates and inhibits allergic rhinitis through KAT2A-mediated histone succinylation.
Study of the mechanism of methyltransferase 3 regulation of ferroptosis in allergic rhinitis and promotion of allergic rhinitis in an m6A-dependent mechanism.
Liu Y, Huo Y, Liu C … +5 more , Yang Y, Li S, Pan X, Wu F, Liu Z
J Inflamm (Lond) · 2025 Nov · PMID 41299698 · Full text
OBJECTIVE: This study aimed to investigate the regulation of allergic rhinitis (AR) by methyltransferase 3 through an m6A-dependent mechanism, providing a theoretical foundation for its treatment. METHODS: An in vitro ex...
OBJECTIVE: This study aimed to investigate the regulation of allergic rhinitis (AR) by methyltransferase 3 through an m6A-dependent mechanism, providing a theoretical foundation for its treatment. METHODS: An in vitro experiment was conducted in which HNEpC cells were stimulated with IL-13 (50 ng/mL) to create an AR cell model. After establishing the AR cell model, the cells were treated with DAA (m6A inhibitor) and separated into three groups: Control group, shNC group and shMETTL3 group.m6A-RIP assessed the m6A modification level of PTBP1 mRNA, while RIP was used to analyze the interaction between METTL3 and PTBP1 mRNA. On the shMETTL3 background, PTBP1 or TXNIP was re-expressed with or without the ferroptosis inhibitor ferrostatin-1 (Fer-1). Endpoints included serum cytokines/immunoglobulins (IFN-γ, IL-1β, IL-18, TGF-β, IL-4, IL-10, IgE, IgG2a, IgG1) and oxidative-stress indices (GSH, SOD, MDA) by ELISA, alongside nasal-mucosa western blots for GPX4, Nrf2, MnSOD, ACSL4, METTL3, PTBP1, and TXNIP. RESULTS: In vitro, shMETTL3 reduced m6A on PTBP1 mRNA and lowered PTBP1 expression. In vivo, the AR condition was associated with higher circulating IFN-γ, IL-1β, IL-18, IL-4, IL-10, IgE, IgG1, and IgG2a, together with lower TGF-β, GSH, and SOD, and a ferroptosis-prone protein profile characterized by reduced GPX4, Nrf2, and MnSOD and increased ACSL4, PTBP1, and TXNIP in nasal mucosa. Silencing METTL3 shifted these readouts toward an anti-oxidant, anti-ferroptotic state, normalizing cytokines/immunoglobulins, raising GSH and SOD while lowering MDA, and restoring a protein pattern with higher GPX4, Nrf2, and MnSOD and lower ACSL4, PTBP1, and TXNIP. Re-expression of PTBP1 or TXNIP on the shMETTL3 background attenuated these improvements and reinstated AR-like oxidative and ferroptotic features. Notably, co-administration of ferrostatin-1 with either overexpression condition re-established antioxidant capacity (higher GSH and SOD with lower MDA) and returned the Western-blot profile toward protection, consistent with a METTL3/PTBP1/TXNIP pathway that promotes ferroptotic and oxidative injury and with the capacity of pharmacologic ferroptosis blockade to counteract it. CONCLUSION: Methyltransferase 3 potentially modulates ferroptosis and oxidative stress linked to AR through an m6A-dependent mechanism, thereby alleviating symptoms in AR mice.
ADRA2A contributes to airway inflammation and apoptosis in asthma through the ERK signaling in vitro and in vivo.
Zhou F, Cai J, Chen L … +2 more , Tan X, Li C
J Inflamm (Lond) · 2025 Nov · PMID 41299456 · Full text
Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness and remodeling, where epithelial dysfunction plays a crucial role. In this study, the role of adrenoceptor alpha 2 A (ADRA2A) in asthma...
Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness and remodeling, where epithelial dysfunction plays a crucial role. In this study, the role of adrenoceptor alpha 2 A (ADRA2A) in asthma was investigated using bioinformatics, in vitro, and in vivo models. Differential gene expression analysis identified ADRA2A was significantly upregulated in asthmatic tissues. BEAS-2B cells treated with lipopolysaccharide (LPS) exhibited increased expression of ADRA2A, along with elevated levels of pro-inflammatory cytokines and apoptosis. Knockdown of ADRA2A in these cells reduced inflammation and apoptosis, while overexpression exacerbated these effects. In an ovalbumin (OVA)-induced asthma mouse model, ADRA2A knockdown led to a significant reduction in airway hyperresponsiveness, pulmonary edema, inflammatory cell infiltration, and goblet cell hyperplasia. The phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), a key signaling pathway involved in inflammation and apoptosis, was also reduced following ADRA2A knockdown, both in vitro and in vivo. In conclusions, these findings suggest that ADRA2A contributes to the pathogenesis of asthma by modulating the ERK signaling pathway, making it a potential therapeutic target for managing airway inflammation and remodeling in asthmatic patients.
Non-invasive assessment of activated renal macrophages by imaging of colony-stimulating factor 1 receptor in mouse model with ischemic acute kidney injury.
Chen S, Zhao X, Li Y … +10 more , Zhang N, Rui X, Guan X, Hu F, Seki C, Xie L, Zhang MR, Tian M, Ji B, Zhou R
J Inflamm (Lond) · 2025 Nov · PMID 41291764 · Full text
BACKGROUND: Emerging evidence suggests that renal inflammation, characterized by the activation of renal macrophages, plays a critical role in the pathogenesis of kidney diseases, including acute kidney injury (AKI). How...
BACKGROUND: Emerging evidence suggests that renal inflammation, characterized by the activation of renal macrophages, plays a critical role in the pathogenesis of kidney diseases, including acute kidney injury (AKI). However, reliable research methods for visualizing renal macrophages remain limited. In this study, we utilized positron emission tomography (PET) imaging combined with a radiolabeled ligand targeting colony-stimulating factor 1 receptor (CSF1R) to assess the potential of CSF1R-PET as a non-invasive tool for examining renal inflammation. METHODS: Single-cell RNA sequencing analysis was performed to identify imaging biomarkers for activated macrophages in an ischemia-reperfusion (I/R)-induced AKI (I/R-AKI) model. We employed PET and in-vitro autoradiography with C-CPPC, a CSF1R-specific radioligand, in mouse models of I/R-AKI and renal/perinephric abscesses (RA). Immunohistochemical analysis was performed to assess renal pathologies, macrophage activation, and CSF1R expression. RESULTS: Single-cell RNA sequencing analysis of publicly available data revealed a dramatic upregulation of CSF1R, primarily expressed in M2 macrophages, in response to I/R-AKI. PET and in-vitro autoradiography showed that retention of C-CPPC was markedly increased in ischemic renal regions and RA-affected areas compared to normal kidney regions. Immunohistochemical analysis confirmed substantial increases in CSF1R expression and the accumulation of activated macrophages in the medullary region of I/R-AKI mice and RA-affected renal regions, supporting the in-vivo and in-vitro imaging results. CONCLUSION: Our findings provide the first evidence supporting the utility of C-CPPC-PET as a clinically-available tool for non-invasive detection of activated renal macrophages, predominantly of the M2 phenotype.
Butyrate ameliorates ulcerative colitis through targeting STING-dependent ER stress signaling and limiting CD4 TRM T cells accumulation.
Xiao T, Kang J, Zhao C … +3 more , Zhu R, Sun M, Wang Y
J Inflamm (Lond) · 2025 Nov · PMID 41286853 · Full text
This study aimed to investigate the role of butyrate in regulating STING-induced endoplasmic reticulum stress (ERS) and CD4 tissue-resident memory (TRM) T cells responses during the progression of ulcerative colitis (UC)...
This study aimed to investigate the role of butyrate in regulating STING-induced endoplasmic reticulum stress (ERS) and CD4 tissue-resident memory (TRM) T cells responses during the progression of ulcerative colitis (UC). Our results demonstrated that butyrate significantly alleviated dextran sulfate sodium (DSS)-induced colitis, as evidenced by restored intestinal epithelial architecture, reduced inflammatory cytokine, and decreased CD4 TRM T cells. These protective effects were likely mediated through modulation of the STING-ERS pathway. Using a CT26 cell model, we further confirmed that STING activation promotes ERS, leading to enhanced secretion of inflammatory factors and subsequent induction of CD4 TRM T cells. Importantly, butyrate effectively suppressed this STING-initiated inflammatory cascade in intestinal epithelial cells (IECs). Our findings revealed a novel mechanism by which butyrate ameliorates UC through inhibition of the STING-ERS axis in IECs, highlighting its therapeutic potential for UC treatment.
Activation of the aryl hydrocarbon receptor relieves acute pancreatitis via the RBX1/HSF1 pathway.
Fang Y, Zhang C, Yu J … +1 more , Shen X
J Inflamm (Lond) · 2025 Nov · PMID 41275289 · Full text
BACKGROUND: Acute pancreatitis (AP) represents one of the most prevalent acute gastrointestinal disorders. Research has indicated a significant correlation between aryl hydrocarbon receptor (AhR) signaling and pancreatic...
BACKGROUND: Acute pancreatitis (AP) represents one of the most prevalent acute gastrointestinal disorders. Research has indicated a significant correlation between aryl hydrocarbon receptor (AhR) signaling and pancreatic injury associated with AP. Nevertheless, the specific role of AhR signaling in tight junction injury induced by AP remains to be fully understood. METHODS: An experimental model of severe AP was established through repeated cerulein injections in conjunction with a single LPS injection. We evaluated pancreatic injury by quantifying serum amylase activity, LDH levels, pancreatic MPO levels, histopathological changes, tight junction protein expression, and the infiltration and polarization of macrophages. The regulatory interactions between AhR and HSF1 were analyzed through experimental validation and predictions derived from the BioGRID and Ubibrowser databases. RESULTS: AhR exhibited low expression and a negative correlation with the M1 polarization of pancreatic resident macrophages (PRM). In primary acinar cells treated with cerulein, AhR enhanced the activation of HSF1 signaling and mitigated the impairment of tight junction integrity. Conditioned medium from primary acinar cells overexpressing AhR resulted in the M2 polarization of PRM. RBX1 was identified as a potential mediator of the interaction between AhR and HSF1. RBX1 was found to facilitate HSF1 ubiquitination through its binding to HSF1, thereby promoting its degradation. Finally, AhR overexpression reduced cerulein/LPS-induced damage to pancreatic tight junction integrity in AP mice, while triptolide inhibited the therapeutic effects. CONCLUSION: AhR facilitates the ubiquitination modification of HSF1 through its interaction with RBX1. This results in the suppression of HSF1 expression and activation, thereby mitigating cerulein/LPS-induced damage to pancreatic tight junctions in AP mice CLINICAL TRIAL NUMBER: Not applicable.
Ferroptosis-related genes MDM2 and CDKN1A as potential biomarkers for COPD.
Shi R, Wang L, Bai C … +5 more , Wang F, Li C, Xiao C, Chen AF, Yang W
J Inflamm (Lond) · 2025 Nov · PMID 41204258 · Full text
OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and an immune response. However, the relationship between ferroptosis and COPD remains unknown. We aim to identify pivotal ferropto...
OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and an immune response. However, the relationship between ferroptosis and COPD remains unknown. We aim to identify pivotal ferroptosis-related biomarkers in COPD and explore their roles in immune infiltration landscapes. METHODS: Differentially expressed genes (DEGs) were obtained from all current datasets of peripheral blood and lung tissues associated with COPD. DEGs were intersected with ferroptosis-related genes (FRGs) from FerrDb database to obtain FRDEGs. Hub FRDEGs were evaluated using WGCNA, GO, and KEGG enrichment, PPI network analysis, LASSO-COX, and ROC curve analysis, and validated in blood of COPD patients. The association between hub FRDEGs and COPD was investigated. The role of hub FRDEGs in 17 types of respiratory tract diseases was analyzed, and potential drugs targeting these FRDEGs were predicted via CMAP drug database. Importantly, MDM2 and CDKN1A expressions were identified and verified by H&E and Masson staining, and Western blot analysis in the CS and LPS-induced COPD mice. RESULTS: MDM2 and CDKN1A were identified as hub genes in all COPD patients, and their expressions were significantly upregulated in the lung tissues of COPD mice. 17 types of respiratory tract diseases were markedly associated with MDM2 and CDKN1A. The 2 genes were correlated with neutrophils. MDM inhibitor (AMG-232) was screened as a potentially key drug affecting MDM2. CONCLUSION: MDM2 and CDKN1A could be potential targets for COPD by regulating neutrophil-involving inflammation. One drug with potential clinical application value was identified.
Lack of phospho-eIF4E worsens experimental colitis by inhibiting Treg suppressive activity.
Santinon F, Papadopoulos T, Berg MH … +11 more , McCallum P, Abraham MJ, Gonçalves C, Gupta V, Gagnon N, Wirasinghe N, Chou H, Esfahani K, Bartish M, Miller WH, Del Rincon SV
J Inflamm (Lond) · 2025 Nov · PMID 41199267 · Full text
BACKGROUND: Phosphorylation of eIF4E by MNK1/2 modulates protein synthesis by controlling the translation of specific mRNAs. Immune cells use the MNK1/2-eIF4E axis to adapt their gene expression in response to environmen...
BACKGROUND: Phosphorylation of eIF4E by MNK1/2 modulates protein synthesis by controlling the translation of specific mRNAs. Immune cells use the MNK1/2-eIF4E axis to adapt their gene expression in response to environmental cues, but its dysregulated activity promotes disease progression. While recent examples using cancer models have identified CD8 T-cells as a conduit for the tumor-supporting role of the MNK1/2-eIF4E axis, the impact of phospho-eIF4E on CD4 T-cell subsets, specifically regulatory T-cells, remains unclear. To fill this knowledge gap, we studied the impact of phospho-eIF4E-deficiency on Treg activity in mice in an inflammatory context using a model of murine colitis and in human PBMCs. RESULTS: We found that Tregs isolated from mice deficient for phospho-eIF4E (expressing a serine-to-alanine mutation at S209) had a diminished ability to control CD4 T-cell proliferation and IFNγ secretion in vitro. We further report aggravated colitis in mice deficient in phospho-eIF4E accompanied by an increase in CD4 T-cells expressing IFNγ and a reduction in Tregs in the mesenteric lymph nodes and colon. Mechanistically, T-cells lacking phospho-eIF4E show impaired differentiation into Tregs, and Tregs lacking phospho-eIF4E have reduced FoxP3 expression and diminished migration to the lymph nodes. Using human PBMCs, anti-CTLA-4, but not anti-PD-1, reduced the phospho-eIF4E-expressing Treg population. CONCLUSIONS: Taken together, these data highlight a role for phospho-eIF4E in Treg biology and in the control of inflammation. CLINICAL TRIAL NUMBER: Not applicable.
Rapid autofluorescence flow cytometric analysis of agonist-induced neutrophil and eosinophil polarization reveals novel insights into 5-oxo-ETE-mediated granulocyte activation.
Fernando AJ, Rossi F, Docherty D … +6 more , Popravko A, Masters L, Houston B, Gupta R, Dhaliwal K, Rossi AG
J Inflamm (Lond) · 2025 Nov · PMID 41199211 · Full text
Minimizing unintended granulocyte activation while measuring functional responsiveness is essential, as the use of external probes, antibodies, or fluorescent dyes can potentially alter cellular responsiveness. To addres...
Minimizing unintended granulocyte activation while measuring functional responsiveness is essential, as the use of external probes, antibodies, or fluorescent dyes can potentially alter cellular responsiveness. To address this, we employed an antibody-free flow cytometry approach that measures forward scatter (FSC) to detect variations in cell-size, morphology, and shape; some key indicators of neutrophil and eosinophil activation. Human peripheral blood neutrophils, containing contaminating eosinophils, were isolated using discontinuous Percoll gradients and pre-treated with receptor antagonists [e.g., cyclosporin-H (an FPR1 antagonist) and CP105696 (a BLT1 receptor antagonist)] prior to stimulation with agonists such as fMLF (an FPR1 agonist) and LTB (a BLT1 agonist). Furthermore, fMLF stimulation resulted in a loss of CD62L and an increase in CD11b expression along with an increase in intracellular ROS production compared to control, as analysed using flow cytometry. Imaging flow cytometry, together with FSC analysis, enabled assessment of cell polarization and associated morphological changes. Importantly, autofluorescence-based gating allowed for the identification of contaminating eosinophils within the mixed granulocyte population, allowing parallel assessment of shape-change in both neutrophils and eosinophils in response to the same ligands. Stimulation of neutrophils with fMLF resulted in distinct FSC shifts compared to unstimulated controls across all flow cytometers tested, which were inhibited by cyclosporin-H, but not CP105696. Morphological analysis confirmed these changes corresponded with increased cell area and perimeter and decreased circularity, hallmarks of cell polarisation. Additionally, selective activation of eosinophils (but not neutrophils) by eotaxin, and dual activation of both cell types by the arachidonic acid metabolite 5-oxo-ETE, were confirmed through specific gating strategies. Taken together, these findings support the use of FSC-based flow cytometry as a rapid, scalable and effective method for evaluating granulocyte polarisation and screening candidate therapeutics targeting immune cell activation in disease contexts.
Correction: The critical role of methylenetetrahydrofolate dehydrogenases in immune regulation and auto-immunity.
Bunyard P, Makrecka-Kuka M, McMillan L
J Inflamm (Lond) · 2025 Oct · PMID 41152845 · Full text
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The critical role of methylenetetrahydrofolate dehydrogenases in immune regulation and auto-immunity.
Bunyard P, Makrecka-Kuka M, McMillan L
J Inflamm (Lond) · 2025 Oct · PMID 41088269 · Full text
1-carbon (1 C) metabolism is a key process required for nucleotide synthesis in activated lymphocytes and other immune-regulatory mechanisms. Commonly used and well-established drugs for the treatment of inflammatory dis...
1-carbon (1 C) metabolism is a key process required for nucleotide synthesis in activated lymphocytes and other immune-regulatory mechanisms. Commonly used and well-established drugs for the treatment of inflammatory disorders such as methotrexate and fluorouracil (5-FU) are known to interact with 1 C metabolism And provide appreciable clinical benefit despite challenges with tolerance And patient compliance. Advances in our understanding of the enzymes involved in 1 C metabolism coupled with differential expression highlights specific targeting of key enzymes may greatly enhance clinical efficacy And reduce side effect burden in comparison to the established therapies that are more indiscriminate in their mode of action. In recent years the methylenetetrahydrofolate dehydrogenase enzymes have gained increasing interest because of the role they play in 1 C metabolism in the immune system and in progression of inflammatory diseases. High expression of these enzymes in activated immune cells and inflamed tissues coupled with chemical tractability provides compelling reasons to actively consider these enzymes as novel therapeutic targets.
Glutaminase activity maintains NK cell cytotoxicity through metabolic regulation of effector function.
Jedlička M, Feglarová T, Švubová V … +9 more , Mašínová E, Graman V, Kuglerová K, Szabová J, Jahan F, Korhonen M, Kuželová K, Hortová-Kohoutková M, Frič J
J Inflamm (Lond) · 2025 Oct · PMID 41088245 · Full text
BACKGROUND: Natural killer (NK) cells are responsible for monitoring and eliminating malignant or virus-infected cells. To become activated, NK cells must upregulate oxidative phosphorylation and glycolysis to meet the h...
BACKGROUND: Natural killer (NK) cells are responsible for monitoring and eliminating malignant or virus-infected cells. To become activated, NK cells must upregulate oxidative phosphorylation and glycolysis to meet the high energetic demands associated with cytotoxic and effector functions. While glutamine can also fuel the tricarboxylic acid cycle through its conversion to alpha-ketoglutarate, the precise role of this pathway in NK-cell cytotoxic activity is unclear. RESULTS: To investigate NK-cell dependency on glutamine, we selectively inhibited kidney-type glutaminase to prevent glutamine metabolism. We analysed the metabolism and cytotoxicity of expanded primary NK cells, treated or not with glutaminase inhibitor. Glutaminase inhibition significantly reduced oxidative phosphorylation and led to a significant decrease in NK cell cytotoxic function. Furthermore, glutaminase inhibition reduced protein synthesis in activated NK cells. Meanwhile, supplementation with alpha-ketoglutarate rescued both the metabolic and cytotoxic capacities of primary expanded NK cells. CONCLUSIONS: Our findings highlight the importance of glutaminase activity in supporting NK cell respiratory metabolism and cytotoxic function, and the need for caution when combining glutaminase inhibitors with NK cell-based therapies.
Effect of heme oxygenase-1 on the expression of interferon-stimulated genes.
Chudy P, Bednarczyk K, Chatian E … +9 more , Krzeptowski W, Szade A, Szade K, Żukowska M, Wolnik J, Sokołowski G, Grochot-Przęczek A, Józkowicz A, Nowak WN
J Inflamm (Lond) · 2025 Oct · PMID 41068867 · Full text
Heme oxygenase-1 (HO1, Hmox1) degrades excess heme and is considered an anti-oxidative and anti-inflammatory enzyme. Our previous studies in Hmox1 knockout mice revealed the induction of interferon-stimulated genes (ISGs...
Heme oxygenase-1 (HO1, Hmox1) degrades excess heme and is considered an anti-oxidative and anti-inflammatory enzyme. Our previous studies in Hmox1 knockout mice revealed the induction of interferon-stimulated genes (ISGs) in all cell types analyzed, despite unchanged interferon production. Here, we sought to determine whether this induction is driven by intrinsic cellular mechanisms or extrinsic cues at the organismal level, and to identify the pathway underlying HO1-dependent ISG regulation. To this end, we analyzed how ISG expression changes in cultured cells exposed to stressors typical of Hmox1 knockout mice. Using murine wild-type and Hmox1-deficient (Hmox1 KO) fibroblasts, we found that under control conditions, the expression of most tested ISGs was independent of cellular HO1 status. We next examined the effects of extrinsic stressors, including hemolytic, oxidative, genotoxic, and replication stress, proinflammatory TNFα, and endogenous heme overload. TNFα, which is upregulated in Hmox1 knockout mice, was the sole and universal inducer of ISGs in both wild-type and Hmox1 KO fibroblasts. Unexpectedly, the response of Hmox1 KO cells to exogenous TNFα was weakened, likely due to impaired NF-κB activity and reduced nuclear retention of the p65 subunit. A similar decrease we observed for STAT1. Additionally, the presence of the TREX1 exonuclease in the nucleus pointed to compromised nuclear envelope integrity in HO-deficient cells. Notably, HO1 colocalizes with PARP1, a protein involved in envelope maintenance and regulation of cytoplasmic-nuclear transport. Inhibition of PARP1 with olaparib dampened TNFα-induced nuclear accumulation of p65 and STAT1 in wild-type cells, but not in Hmox1 KO counterparts. In summary, the inflammation observed in Hmox1-deficient mice appears to be the main cell-extrinsic driver of ISG induction in vivo. Despite this, the inflammatory response to exogenous TNFα is intrinsically attenuated in Hmox1 KO cells, likely due to decreased nuclear retention of NF-κB and STAT1.
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