Inflammation Research[JOURNAL]
Sun
200 papers
JAK/STAT inhibition reprograms T cell activation and metabolism in inflammatory arthritis patients.
Marzaioli V, Brugman AAI, O'Dowd N … +5 more , Floudas A, Gorman A, Orr C, Veale DJ, Fearon U
Inflamm Res · 2026 May · PMID 42084739 · Full text
OBJECTIVES: Inflammatory arthritis (IA) is a group of autoimmune diseases characterised by joint inflammation and progressive damage, thus impairing the patient's quality of life. The JAK/STAT pathway inhibitor Tofacitin...
OBJECTIVES: Inflammatory arthritis (IA) is a group of autoimmune diseases characterised by joint inflammation and progressive damage, thus impairing the patient's quality of life. The JAK/STAT pathway inhibitor Tofacitinib has been successfully introduced into the clinic to treat patients with IA, however its direct effect on T cell responses is widely unknown. This study aims to assess the effect of Tofacitinib on T cell activation, polyfunctionality, proliferation and metabolism. METHODS: The effect of Tofacitinib on T cells from peripheral blood, synovial fluid and synovial tissue was evaluated with multidimensional flow cytometric analysis. T cell proliferation was assessed by flow cytometry and T cell metabolism was examined by qPCR and Seahorse XF analyser. To investigate the effect of Tofacitinib on T cell polarisation, naïve T cells were differentiated into Th1, Th2 and Th17 with specific cytokine cocktails. Soluble mediators were evaluated by MSD multiplex analysis. RESULTS: Tofacitinib significantly inhibited T helper cell activation as evidenced by a marked reduction in the frequency of PD-1/CD69/CD25-positive cells (p < 0.01). Reduced activation was consistent with impairment of pathogenic polyfunctionality of peripheral blood and synovial tissue-derived T cells. The impact of Tofacitinib on T cell plasticity was further substantiated by reduced T cell polarisation towards Th1 (p < 0.05), Th2 (p < 0.05), Th17 (p < 0.05) and a reduction in genes associated with T cell functions. The attenuation of pathogenic T cell responses is linked to metabolic adaptation, with Tofacitinib leading to a switch in metabolic capacity, mainly ascribed to the CD4CD8 T cell compartment. CONCLUSIONS: Tofacitinib strongly alters T cell responses and potentially limits T cell pathogenicity by decreasing their activation, polyfunctionality, differentiation, and metabolic potential in both the circulation and the joints of patients with inflammatory arthritis.
Integrated multi-omics profiling reveals the potential role of maternal systemic immune dysregulation driven by monocyte/macrophage in preeclampsia.
Yuan X, Han K, Zhan X … +5 more , Qi Y, Yang S, Li Y, Zhang S, Chen K
Inflamm Res · 2026 Apr · PMID 42050225 · Publisher ↗
BACKGROUND: Preeclampsia (PE) is a leading cause of maternal morbidity and mortality, but the coordinated dysregulation between the placental unit and the maternal systemic immune response remains incompletely understood...
BACKGROUND: Preeclampsia (PE) is a leading cause of maternal morbidity and mortality, but the coordinated dysregulation between the placental unit and the maternal systemic immune response remains incompletely understood. An integrated multi-omics approach is required to decipher these cross-tissue interactions. METHODS: We performed an integrated analysis of bulk transcriptome data from 810 pregnancies (299 placental tissues and 511 blood samples). Additionally, to gain mechanistic insights at cellular resolution, we analyzed single-cell RNA sequencing (scRNA-seq) data from maternal endometrial biopsies (from non-pregnant women with a history of PE or Normal, n = 21) and peripheral blood mononuclear cells (PBMCs, n = 10). Analytical methods included differential expression analysis, pathway enrichment, machine learning-based predictive modeling, and cell–cell communication inference. RESULTS: Analysis of bulk transcriptomes from placental and blood specimens identified 25 core genes consistently associated with PE. A Random Forest model constructed with these genes demonstrated high predictive accuracy (AUC > 0.96 in both tissue and blood) and was validated in an independent cohort (AUC = 0.775). To explore the cellular basis of this signature, we turned to scRNA-seq data. Analysis of maternal endometrium and PBMCs identified a reconfigured immune microenvironment, characterized by an increased proportion of LYZ + monocytes in endometrium from women with a history of PE. A key finding was the significant downregulation of the coagulation factor F13A1 within monocyte/macrophage lineages across both bulk and single-cell datasets. Cell–cell communication analysis further suggested that monocytes/macrophages may regulate immune and endothelial cells through dysregulated COMPLEMENT and GALECTIN signaling pathways. CONCLUSION: Our study defines a robust, placenta-blood based gene signature for PE. Exploratory analysis of maternal endometrial and immune cells at single-cell resolution provides preliminary evidence that monocyte/macrophage dysfunction, including F13A1 downregulation, may be a pervasive feature of PE pathophysiology, observable even in maternal tissues beyond the placenta. These findings highlight the potential of cross-tissue biomarkers and justify further investigation into the systemic role of myeloid cells in PE.
Glucocorticoids combined with anticoagulation modulate the central NLRP3/NETosis inflammatory process in patients with severe cerebral venous thrombosis: a human mechanistic exploratory study.
Li Y, Ying C, Wang X … +4 more , Zhang M, Hu S, Cai Y, Duan J
Inflamm Res · 2026 Apr · PMID 42050165 · Publisher ↗
OBJECTIVES: Neutrophil-mediated neuroinflammation plays a crucial role in secondary brain injury following severe cerebral venous thrombosis (CVT). Although previous studies have reported that the combination of glucocor...
OBJECTIVES: Neutrophil-mediated neuroinflammation plays a crucial role in secondary brain injury following severe cerebral venous thrombosis (CVT). Although previous studies have reported that the combination of glucocorticoids (GCs) and anticoagulation is associated with improved clinical outcomes, its mechanism remains unknown. We hypothesized that the combination therapy may exert benefit by modulating neutrophil-driven inflammation. METHODS: This study included a cohort of 50 patients diagnosed with severe CVT who were undergoing treatment with the combination therapy. We investigated the dynamic alterations in the NLRP3/NETosis inflammatory process by analyzing paired serum and cerebrospinal fluid (CSF) samples collected at baseline and 1 week post-treatment. Neurological function was systematically evaluated using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). RESULTS: The combined therapy was associated with reduced CSF levels of key NLRP3/NETosis mediators, including NOD-like receptor family pyrin domain containing 3 (NLRP3), polymorphonuclear neutrophil elastase (PMN Elastase), myeloperoxidase (MPO), and citrullinated histone H3 (CitH3), while the corresponding serum levels were unchanged. Baseline CSF levels of NLRP3, PMN Elastase, and MPO strongly correlated with admission NIHSS and mRS. Early reductions in these central markers were associated with neurological improvement at discharge (ΔNIHSS). Moreover, patients with unfavorable outcomes (discharge mRS > 1) had significantly higher baseline NIHSS and CSF NLRP3 levels. CONCLUSIONS: The combined therapy may alleviate severe CVT by modulating the central NLRP3/NETosis inflammatory process.
Regulated cell death in sepsis: reframing NETosis within the spectrum of apoptosis and inflammatory lytic death.
Iba T, Okada H, Nagaoka I … +2 more , Ferrer R, Levy JH
Inflamm Res · 2026 Apr · PMID 42050159 · Publisher ↗
BACKGROUND: Sepsis is characterized by dysregulated inflammation leading to organ dysfunction. While immune activation and metabolic stress are central features, accumulating evidence suggests that regulated cell death p...
BACKGROUND: Sepsis is characterized by dysregulated inflammation leading to organ dysfunction. While immune activation and metabolic stress are central features, accumulating evidence suggests that regulated cell death programs actively influence inflammatory trajectories rather than serving as passive end-stage events. Apoptosis, pyroptosis, necroptosis, ferroptosis, and neutrophil extracellular trap (NET) formation have each been implicated in sepsis; however, their relative hierarchy, temporal dynamics, and compartment-specific relevance remain incompletely defined. OBJECTIVE: To synthesize current evidence on regulated cell death pathways in sepsis and to propose a phase-specific and compartment-oriented framework that integrates apoptotic, inflammatory lytic, and NET-associated mechanisms within a unified inflammatory model. METHODS: A narrative review of experimental, translational, and clinical studies examining apoptosis, pyroptosis, necroptosis, ferroptosis, PANoptosis, and NETosis in sepsis and related inflammatory states was conducted. Emphasis was placed on signaling dependency, inflammatory consequences, temporal phase distinctions, and cellular compartment heterogeneity. RESULTS: Apoptosis remains the dominant leukocyte death program associated with late-phase immune depletion and immunosuppression. In contrast, inflammasome-mediated pyroptosis and RIPK1/RIPK3-dependent necroptosis amplify early hyperinflammatory responses by inducing membrane permeabilization and damage-associated molecular pattern release. Ferroptosis represents an emerging iron-dependent metabolic-inflammatory interface with potential organ-specific relevance, although clinical validation remains limited. NET formation, often interpreted as a distinct death program, is more appropriately understood as a context-dependent effector mechanism linking innate immunity to thromboinflammation rather than representing the predominant terminal fate of leukocytes in sepsis. Increasing evidence supports pathway crosstalk and PANoptotic integration, suggesting that regulated cell death programs function as overlapping inflammatory networks rather than isolated processes.
The ubiquitin ligase FBXW7 regulates epithelial pyroptosis in severe asthma.
Jiang Y, Ji T, Ren X … +4 more , Gu Y, Xu X, Chen E, Li H
Inflamm Res · 2026 Apr · PMID 42050150 · Publisher ↗
BACKGROUND: Severe asthma is characterized by persistent airway inflammation and epithelial injury. Pyroptosis, a Caspase-1-dependent inflammatory cell death pathway, has been implicated in airway inflammation. FBXW7, an...
BACKGROUND: Severe asthma is characterized by persistent airway inflammation and epithelial injury. Pyroptosis, a Caspase-1-dependent inflammatory cell death pathway, has been implicated in airway inflammation. FBXW7, an E3 ubiquitin ligase involved in inflammatory regulation, may play a role in this process; however, its function in severe asthma remains unclear. METHODS: Human microarray datasets from the Gene Expression Omnibus (GEO) were analyzed to identify differentially expressed genes and potential biomarkers using bioinformatics and machine learning approaches. Experimental validation was performed using murine asthma models, including ovalbumin (OVA)-induced and OVA/LPS-induced models. Airway epithelium-specific FBXW7 conditional knockout mice were generated to assess in vivo function. In vitro, murine lung epithelial (MLE12) cells with FBXW7 knockout or overexpression were used to evaluate pyroptosis and inflammatory responses following LPS/ATP stimulation. Cytokine levels, Caspase-1 expression, and signaling pathways were analyzed using ELISA, Western blotting, and immunofluorescence. RESULTS: FBXW7 expression was significantly decreased in severe asthma compared with mild-to-moderate asthma, while Caspase-1 expression was increased. Machine learning analyses identified FBXW7 and Caspase-1 as potential biomarkers in severe asthma. In murine models, FBXW7 downregulation was more pronounced in severe asthma and was associated with increased inflammatory cell infiltration and cytokine production. FBXW7-deficient mice exhibited significantly elevated bronchoalveolar lavage fluid (BALF) inflammatory cell counts and increased IL-1β secretion compared with wild-type controls. In vitro experiments using MLE12 cell lines with FBXW7 overexpression, knockout, and wild-type backgrounds exhibited significant differences in Caspase-1 expression and altered secretion of inflammatory cytokines IL-18 and IL-1β under LPS/ATP-induced pyroptotic conditions, while pharmacological inhibition of Caspase-1 corrected aberrant cytokine secretion. However, mRNA levels of these cytokines remained stable, indicating that FBXW7 controls IL-18/IL-1β maturation/secretion via Caspase-1. Thus, the association among FBXW7, Caspase-1 and cGAS-STING was tested. CONCLUSIONS: FBXW7 suppresses airway epithelial pyroptosis and inflammation in severe asthma by regulating Caspase-1, potentially via the cGAS-STING pathway. These findings highlight FBXW7 as a potential biomarker for severe asthma.
The role of neutrophils in the pathogenesis of abdominal aortic aneurysms.
Addo SA, Wojnar-Lason K, Sreekumar A … +3 more , Roy T, Sloan D, Csányi G
Inflamm Res · 2026 Apr · PMID 42050119 · Full text
BACKGROUND: Abdominal aortic aneurysm (AAA) is a progressive degenerative vascular disease characterized by structural weakening and pathological dilatation of the abdominal aortic wall. Currently, no effective pharmacol...
BACKGROUND: Abdominal aortic aneurysm (AAA) is a progressive degenerative vascular disease characterized by structural weakening and pathological dilatation of the abdominal aortic wall. Currently, no effective pharmacological therapies are available, and treatment remains largely limited to surgical intervention. This underscores the urgent need to better understand the mechanisms driving disease development and progression. Among the cellular mediators implicated in AAA, neutrophils have emerged as key contributors to vascular inflammation and tissue destruction. METHODS: We performed a comprehensive literature review of original research articles and relevant reviews addressing the role of neutrophils in AAA pathogenesis. Studies were identified through systematic searches of major databases, including PubMed and Google Scholar, using the keywords "abdominal aortic aneurysm", "neutrophils", "vascular inflammation", "oxidative stress", "proteases", and "extracellular matrix degradation". Both experimental and clinical studies were included to provide an integrated overview of current knowledge in the field. RESULTS: Accumulating evidence indicates that neutrophils actively infiltrate the aortic wall during AAA development, where they release a diverse array of effector molecules, including reactive oxygen species, proteolytic enzymes, pro-inflammatory cytokines, chemotactic mediators, and granule proteins. Collectively, these mediators sustain chronic vascular inflammation, promote extracellular matrix degradation, and contribute to progressive structural weakening of the arterial wall. This review summarizes both established and emerging roles of neutrophils in AAA pathogenesis, with a particular focus on their contribution to vascular inflammation, thereby providing a conceptual framework for future diagnostic and therapeutic development. CONCLUSION: Neutrophils are central regulators of AAA pathogenesis through their multifaceted roles in vascular inflammation and extracellular matrix remodeling. Targeting neutrophil activation and downstream inflammatory pathways may represent a promising therapeutic strategy. A deeper mechanistic understanding of neutrophil-driven processes may facilitate the development of novel biomarkers and pharmacological approaches aimed at limiting AAA progression and preventing rupture.
Renin-angiotensin imbalance promotes excessive fibrin deposition through M2 macrophage-derived tissue factor expression in eosinophilic chronic rhinosinusitis.
Takabayashi T, Yoshida K, Kato Y … +2 more , Sakashita M, Fujieda S
Inflamm Res · 2026 Apr · PMID 42050086 · Full text
BACKGROUND: Recalcitrant nasal polyps are hallmarks of eosinophilic chronic rhinosinusitis, with abnormal fibrin deposition being critical for nasal polyp development. However, the specific cellular and molecular mechani...
BACKGROUND: Recalcitrant nasal polyps are hallmarks of eosinophilic chronic rhinosinusitis, with abnormal fibrin deposition being critical for nasal polyp development. However, the specific cellular and molecular mechanisms underlying the pathogenesis of nasal polyps in patients with eosinophilic chronic rhinosinusitis remain poorly understood. To assess the impact of the renin-angiotensin system on eosinophilic chronic rhinosinusitis pathogenesis and identify new therapeutic targets. METHODS: Renin-angiotensin system components, fibrin, tissue factor, and macrophages in nasal tissues were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, and immunofluorescence. Gene expression and protein levels were also analyzed in cultured THP-1 cells. RESULTS: In eosinophilic chronic rhinosinusitis nasal polyps, angiotensin-converting enzyme 2, Mas receptor, and angiotensin (1-7) were significantly reduced, while angiotensin II receptor type 1 was increased compared to non-eosinophilic chronic rhinosinusitis nasal polyps. This suggests angiotensin II/angiotensin II receptor type 1 axis predominance over the angiotensin (1-7)/Mas receptor axis in eosinophilic chronic rhinosinusitis. Immunofluorescence revealed profound fibrin deposition and increased tissue factor levels in eosinophilic chronic rhinosinusitis nasal polyps. M2 macrophages (CD68 + /CD163 +) were highly infiltrated, with most expressing tissue factor. Tissue factor expression was significantly increased in M2-polarized macrophages, and co-stimulation with angiotensin II further enhanced this expression. CONCLUSION: Renin-angiotensin system dysregulation might contribute to nasal polyp development in patients with eosinophilic chronic rhinosinusitis. Angiotensin II/angiotensin II receptor type 1 axis predominance over the angiotensin (1-7)/Mas receptor axis may enhance fibrin deposition by enhancing tissue factor expression in M2 macrophages, contributing to recalcitrant nasal polyp formation.
Lp-PLA2-derived LysoPC drives dendritic cell immunogenic activation and Th17 inflammation in severe asthma.
Wang F, Min Z, Qian Y … +4 more , Gao J, Yang Z, Jiang Z, Chen Z
Inflamm Res · 2026 Apr · PMID 42049997 · Publisher ↗
Severe asthma (SA) is associated with dysregulated phospholipid metabolism, yet the underlying immunometabolic mechanisms remain poorly understood. Our metabolomic profiling of SA patients revealed a characteristic remod...
Severe asthma (SA) is associated with dysregulated phospholipid metabolism, yet the underlying immunometabolic mechanisms remain poorly understood. Our metabolomic profiling of SA patients revealed a characteristic remodeling of the phosphatidylcholine (PC)-lysophosphatidylcholine (LysoPC) axis, featuring an accumulation of long-chain PC precursors and a depletion of polyunsaturated lipids. In a murine model of severe neutrophilic asthma, we identified explosive localized generation of pathogenic saturated LysoPC (particularly the 16:0 species) driven by hyperactive PC hydrolysis. Mechanistically, LysoPC acts as an endogenous danger signal that promotes the immunogenic activation of dendritic cells (DCs) by inducing a signaling "seesaw" of concurrent NF-κB activation and p38 MAPK suppression, thereby driving na ïve CD4 T cells toward a Th17 phenotype. Crucially, the expression of lipoprotein-associated phospholipase A2 (Lp-PLA2) was robustly upregulated in both murine and human monocyte-derived DCs (moDCs) from SA patients. Importantly, pharmacological inhibition of Lp-PLA2 with darapladib reduced Th17-mediated neutrophilic inflammation in a steroid-resistant asthma model and suppressed DC immunogenicity in vitro. Collectively, our findings define the Lp-PLA2/LysoPC axis as a novel driver of DC-mediated Th17 inflammation, highlighting this pathway as a promising therapeutic target for severe asthma.
Mechanistic insights into natural product-driven modulation of NLRP3-inflammasome signalling in metabolic syndrome.
Sahariah P, Saikia L, Bharali A … +4 more , Law D, Sen S, Sivasamugham LA, Dutta PP
Inflamm Res · 2026 Apr · PMID 42049985 · Publisher ↗
INTRODUCTION: Metabolic syndrome (MetS) comprises a cluster of interrelated metabolic abnormalities, including obesity, insulin resistance, dyslipidaemia and hypertension, mainly driven by chronic low-grade inflammation....
INTRODUCTION: Metabolic syndrome (MetS) comprises a cluster of interrelated metabolic abnormalities, including obesity, insulin resistance, dyslipidaemia and hypertension, mainly driven by chronic low-grade inflammation. Among innate immune pathways, the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has emerged as a critical molecular link between metabolic stress and inflammatory signalling, promoting caspase-1 activation, interleukin (IL)-1β/IL-18 maturation and pyroptosis across metabolically active organs such as adipose tissue, liver and pancreas. Persistent NLRP3 activation, triggered by mitochondrial dysfunction, oxidative stress, ionic imbalance and impaired autophagy, contributes directly to insulin resistance, hepatic steatosis, β-cell dysfunction and cardiometabolic complications, highlighting natural products as promising multi-target modulators capable of attenuating NLRP3-driven metabolic inflammation. METHODS: The literature search was conducted in PubMed and Scopus to identify recent studies investigating phytochemical-mediated modulation of NLRP3 inflammasome signalling in MetS from 2020 to December 2025. Eligible studies were screened for mechanistic relevance, with particular emphasis on NLRP3-centred pathways. RESULTS AND CONCLUSION: The consolidated evidence demonstrates that diverse classes of natural products, including flavonoids, phenolic acids, terpenoids and other bioactive compounds, effectively attenuate NLRP3 activation by suppressing NF-κB-dependent priming, limiting mitochondrial ROS generation, stabilising lysosomal integrity, enhancing AMPK-SIRT signalling and promoting autophagy. Several plant extracts and complex formulations exhibit coordinated metabolic and anti-inflammatory benefits across adipose, hepatic, vascular, neural and renal models of MetS. In addition to summarising their regulatory effects on key inflammatory and metabolic pathways, the review also addresses available toxicity and safety data, thereby providing a more comprehensive perspective on their therapeutic relevance. Overall, this review presents an integrated synthesis of mechanistic and preclinical evidence highlighting natural products as multi-target modulators of NLRP3-mediated metabolic inflammation.
Targeting angiopoietin-like protein 3 and interleukin-1β alleviated liver and kidney injury through attenuation of lipotoxicity and regulation of glycolipid metabolism in db/db mice.
Xu S, Wang L, Dou Z … +16 more , Hu X, Cao Z, Zhang Y, Jiang X, Wu T, Li Z, Nan Y, Zhu A, Bai Y, Zou Z, Zhang X, Zeng X, He H, Wang S, Ju D, Fan J
Inflamm Res · 2026 Apr · PMID 41998441 · Publisher ↗
OBJECTIVE: Concomitant liver and kidney injury is a critical pathological feature of metabolic disorders, but current organ-specific therapies often fail to provide cross-protection. Lipotoxicity is a core mechanism link...
OBJECTIVE: Concomitant liver and kidney injury is a critical pathological feature of metabolic disorders, but current organ-specific therapies often fail to provide cross-protection. Lipotoxicity is a core mechanism linking damage in both organs. Therefore, this study aimed to investigate whether simultaneously targeting ANGPTL3 and IL-1β could attenuate lipotoxicity and thereby ameliorate concomitant liver and kidney injury. METHODS: A novel bispecific antibody (BsAb) targeting both ANGPTL3 and IL-1β was generated and characterized by SDS-PAGE, SEC-HPLC, thermal stability analysis, SPR and in vitro bioassay. Then, its protective effects were subsequently studied in the db/db mouse model and the underlying mechanisms were revealed by biochemical examinations, histopathological analysis, immunofluorescence (IF), ELISA, RNA-seq. RESULTS: Administration of the BsAb in db/db mice effectively improved liver and kidney function with alleviated liver steatosis and inflammation, as well as reduced kidney glomerular injury. Furthermore, the treatment attenuated lipotoxicity in both organs and ameliorated glycolipid metabolism disturbance including restored hepatic glycogen reserves and enhanced renal utilization of fatty acids. CONCLUSION: The results demonstrate that the anti-ANGPTL3/IL-1β BsAb alleviates concomitant liver and kidney injury in db/db mice by attenuating lipotoxicity and regulating glycolipid metabolism, which highlights a promising therapeutic approach for addressing multi-organ damage in metabolic disorders.
Macrophages with ITIH4 overexpression attenuate inflammatory responses and regulate intestinal epithelial cells.
Li J, Zhao Z, Fei J … +5 more , Zhang R, Pan L, Xiang Y, Hong L, Zhan Z
Inflamm Res · 2026 Apr · PMID 41998424 · Publisher ↗
OBJECTIVE: Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is an acute phage protein and secretory protein that is highly related to inflammation. However, the expression profile and function of ITIH4 in macrophage-m...
OBJECTIVE: Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is an acute phage protein and secretory protein that is highly related to inflammation. However, the expression profile and function of ITIH4 in macrophage-mediated inflammation are still unclear. METHODS: Quantitative proteomics based on mass spectrometry was performed to explore differential protein expression in bone marrow-derived macrophages (BMDMs) subjected to the indicated treatments. Western blot and qRT-PCR assays were performed to confirm the expression of ITIH4 in macrophages. ITIH4 was overexpressed and knocked down in Raw264.7 cells, and ITIH4 was knocked down in THP-1 cells, after which the function and molecular mechanism of ITIH4 in macrophages were investigated. Immunohistochemical staining and online bioinformatics tools were used to explore the expression of ITIH4 in the inflamed colon. In addition, CCK8, scratch wound healing, RNA-seq, qRT-PCR and Western blot assays were performed to explore the function and mechanism of macrophages with ITIH4 overexpression in colonic epithelial cells. RESULTS: Our findings demonstrated that the expression of full-length ITIH4 increased in pro-inflammatory macrophages resulting from a decrease in cleavage, whereas treatment with 4-octyl itaconate (OI) promoted the synthesis and secretion of full-length ITIH4. We overexpressed or knocked down ITIH4 in macrophages, subsequently revealed that ITIH4 modulated anti-inflammatory responses via the NF-κB signaling pathway in macrophages. Moreover, macrophages with ITIH4 overexpression activated cAMP signaling pathway to enhance the viability and tight junction integrity of colonic epithelial cells. CONCLUSION: This study suggests that ITIH4 plays crucial roles in the inflammatory response of macrophages and may be an important molecule that regulates macrophage-epithelium interactions. Our findings shed new light into the molecular mechanism underlying macrophage drives intestinal inflammation and highlight ITIH4 as a therapeutic target for mitigating macrophages-induced intestinal damage.
The calcium-sensing receptor in sepsis and septic shock, mechanistic pathways and translational perspectives: a systematic review.
Janssen V, Kamel S, Slama M … +4 more , Abou-Arab O, Brazier M, Mentaverri R, Mary A
Inflamm Res · 2026 Apr · PMID 41998370 · Full text
BACKGROUND: Sepsis and septic shock are major causes of mortality in critically ill patients. They are linked to widespread metabolic and immune dysregulation, including alterations in calcium and phosphate homeostasis....
BACKGROUND: Sepsis and septic shock are major causes of mortality in critically ill patients. They are linked to widespread metabolic and immune dysregulation, including alterations in calcium and phosphate homeostasis. The calcium-sensing receptor (CaSR) not only plays a role in mineral balance, but also modulates key immune pathways and may contribute to the pathogenesis of sepsis. METHODS: A systematic literature review was conducted according to PRISMA 2020 guidelines. Four databases (PubMed, EMBASE, Cochrane Library, and Google Scholar) were searched for studies published since 1990. To be eligible for inclusion, articles had to be original research, reviews, or clinical trials involving adult models (mammalian or human). Full-text availability was required. Risk of bias was assessed for all studies included. RESULTS: Sixty-six articles met the inclusion criteria: 49 original studies and 17 reviews. No randomized controlled trials or meta-analyses were identified. Most studies relied on in vitro or in vivo models. CaSR was consistently reported to be upregulated or activated following exposure to bacterial and inflammatory stimuli in immune cells, including monocytes and lymphocytes. CaSR activation promotes proinflammatory cytokine release, notably IL-1β via the NOD like receptor family 3 (NLRP3) inflammasome although results in intestinal epithelial models remain inconsistent. In non-septic models, CaSR activation was associated with tissue and organ injury, including renal and cardiac damage, as well as vasoplegia related to endothelial dysfunction. Preclinical models of pneumonia and endotoxemia suggest that CaSR antagonists may effectively mitigate inflammation and organ injury. CONCLUSION: This systematic review identifies the CaSR as an amplifier of the host inflammatory response across both septic and non-septic preclinical models The lack of robust clinical data underscores the need for translational studies assessing CaSR expression or activity in patients with sepsis or septic shock, alongside in vivo validation of CaSR inhibition as a therapeutic strategy.
Imiquimod enhances anti-tumor effects of CD47 targeting in oral squamous cell carcinoma.
He H, Hao Y, Chen J … +5 more , Ren B, Zheng X, Cao X, Li B, Cheng L
Inflamm Res · 2026 Apr · PMID 41998354 · Publisher ↗
OBJECTIVES: Regarding the limited clinical curative efficacy of CD47-targeted immunotherapy in treating oral squamous cell carcinoma (OSCC), the project aims to study the effect and mechanism of imiquimod-enhanced CD47 t...
OBJECTIVES: Regarding the limited clinical curative efficacy of CD47-targeted immunotherapy in treating oral squamous cell carcinoma (OSCC), the project aims to study the effect and mechanism of imiquimod-enhanced CD47 targeting in treating OSCC. METHODS: The effect of imiquimod on enhancing the phagocytosis and clearance of OSCC cells of CD47 targeting was studied through phagocytosis experiments and cell clearance experiments. Then, the safety of the local application of imiquimod was confirmed, and the effect of imiquimod was verified in vivo by immunohistochemistry staining and tumor growth analysis. Finally, transcriptome sequencing, macrophage polarization, phagocytosis experiments, and cell clearance experiments were used to study the mechanism of imiquimod-enhanced CD47 targeting for treating OSCC. RESULTS: Imiquimod significantly enhances the phagocytosis and removal of OSCC cells when combined with CD47 targeting. In vivo studies have confirmed its capacity to potentiate CD47 targeting and revealed good biosafety of imiquimod. Mechanistically, imiquimod promotes M1 macrophage polarization by activating the Toll-like receptor (TLR)7-nuclear factor (NF)-κB pathway in macrophages. This activation enhanced the phagocytic capacity of macrophages to effectively remove OSCC cells. CONCLUSIONS: Imiquimod enhances CD47 targeting in phagocytosing and removing OSCC cells by activating macrophage TLR7-NF-κB activation and subsequent M1 polarization, providing a promising approach for treating OSCC.
Tm4sf19 inhibition alleviates imiquimod-induced psoriatic dermatitis by regulating inflammatory signaling pathways and keratinocyte proliferation in mice.
Kang MG, Park S, Hong E … +17 more , Lee MJ, Jung DS, Heo JS, An H, Kim MW, Park N, Park H, Kim P, Son M, Pang K, Park J, Hwang GE, Kwon YJ, Mizuno S, Takahashi S, Park SH, Kim SJ
Inflamm Res · 2026 Apr · PMID 41998341 · Publisher ↗
BACKGROUND: Psoriasis is a chronic inflammatory disease characterized by keratinocyte hyperproliferation, immune cell infiltration, and persistent inflammatory signaling. Although Tm4sf19 has been implicated in inflammat...
BACKGROUND: Psoriasis is a chronic inflammatory disease characterized by keratinocyte hyperproliferation, immune cell infiltration, and persistent inflammatory signaling. Although Tm4sf19 has been implicated in inflammatory processes, its contribution to psoriasis pathogenesis remains unclear. METHODS: We investigate the role of Tm4sf19 in psoriatic inflammation was examined using an imiquimod-induced psoriasis mouse model and HaCaT keratinocytes, in which Tm4sf19 expression was deleted genetically or suppressed pharmacologically with the competitive inhibitor, LEL-Fc. Gene expression, protein expression, and tissue changes were assessed by qPCR, western blotting and histological scoring, respectively. RESULTS: Tm4sf19 expression was significantly elevated in psoriatic lesion. Tm4sf19 knockout or inhibition using LEL-Fc suppressed psoriatic symptoms, macrophage-mediated inflammation and inflammatory cytokine expression. Tm4sf19 inhibition also suppressed the activation of STAT3, EGFR, ERK and KRT17 signaling pathways in keratinocytes. Furthermore, LEL-Fc treatment effectively inhibited LPS-induced cell cycle progression and promoted apoptosis in keratinocyte both in vivo and in vitro. CONCLUSION: These findings suggest that Tm4sf19 regulates psoriatic inflammation and keratinocyte proliferation through major signaling pathways. Therefore, inhibiting Tm4sf19 may have therapeutic potential for the treatment of psoriasis.
Dynamic risk stratification in burn sepsis: methodological considerations and path forward.
Jiang B, Liu H
Inflamm Res · 2026 Apr · PMID 41998330 · Publisher ↗
BACKGROUND: Lou et al. recently reported that longitudinal trajectories of albumin, IL-6, and immunoglobulin G define three distinct prognostic phenotypes in burn patients with sepsis, with markedly divergent 21‑day mort...
BACKGROUND: Lou et al. recently reported that longitudinal trajectories of albumin, IL-6, and immunoglobulin G define three distinct prognostic phenotypes in burn patients with sepsis, with markedly divergent 21‑day mortality. OBJECTIVE: To critically evaluate the methodological framework of the study and propose constructive refinements to enhance clinical translatability. FINDINGS: While the trajectory-based phenotyping represents a significant advance, four areas warrant attention: (1) the choice of clustering markers-albumin's sensitivity to fluid shifts and the omission of cellular immune markers may limit phenotypic resolution; (2) the requirement for complete longitudinal data introduces survivorship bias that joint modeling could address; (3) time‑varying clinical interventions likely modify biomarker trajectories and should be incorporated; and (4) early prediction algorithms are needed to enable phenotype assignment within the first days of admission. CONCLUSION: Addressing these considerations would strengthen the robustness of the proposed phenotypes and accelerate their integration into dynamic, personalized management strategies for burn sepsis.
Roles of mitophagy and immune infiltration in Parkinson's disease: new perspectives from bioinformatics analysis and A53T transgenic mice.
Li X, Zhang Y, Yang Q … +7 more , Gong J, Zhang N, Huang Y, Chen T, Zhou D, Zou Z, Guo Z
Inflamm Res · 2026 Apr · PMID 41998308 · Publisher ↗
BACKGROUND: Mitophagy plays a critical role in the pathology of Parkinson's disease (PD) via mitochondrial quality control, making it a promising therapeutic target. However, the precise mechanistic role of mitophagy in...
BACKGROUND: Mitophagy plays a critical role in the pathology of Parkinson's disease (PD) via mitochondrial quality control, making it a promising therapeutic target. However, the precise mechanistic role of mitophagy in PD pathogenesis and progression remains unclear. METHODS: We conducted a bioinformatic analysis to identify hub mitophagy-related differentially expressed genes (hub-MPDEGs). The mRNA expression levels of these identified genes were validated using two single-cell RNA sequencing datasets (GSE178265 and PRJNA1145007) and further confirmed in an α-synuclein A53T transgenic mouse model. RESULTS: Five hub-MPDEGs were identified: CANX, GABARAPL1, HSPD1, PPARGC1A, and TOMM20. Transcriptomic analysis revealed elevated abundance of these genes in α-synuclein A53T mice compared to controls. Single-cell resolution analysis demonstrated significant differential expression of these genes in astrocytes, dopamine neurons, glutamatergic neurons, endothelial cells, and oligodendrocyte precursor cells within the substantia nigra of PD samples compared to controls. Furthermore, significant differences in mRNA levels were observed in peripheral immune cells, specifically CD4+ T cells, CD8+ T cells, monocytes, and NK cells, between control and PD samples. CONCLUSIONS: This study identifies and validates five key mitophagy-related genes that are differentially regulated in the central nervous system and peripheral immune cells in the context of Parkinson's disease. These findings highlight the systemic nature of mitophagy dysregulation in PD.
Personalizing treatment of pancreatitis-associated chronic pain: the need for an integrated omics approach.
Myers C, Espinoza CM, Clarke A … +8 more , Lusczek ER, Xie F, Steffen BT, C Nwosu Z, Trikudanathan G, Saarunya G, Bellin M, Beilman G
Inflamm Res · 2026 Apr · PMID 41998114 · Full text
BACKGROUND: Chronic pancreatitis (CP) is a progressive inflammatory disorder characterized by debilitating chronic pain and substantial healthcare burden. Pain mechanisms in CP are heterogeneous and incompletely integrat...
BACKGROUND: Chronic pancreatitis (CP) is a progressive inflammatory disorder characterized by debilitating chronic pain and substantial healthcare burden. Pain mechanisms in CP are heterogeneous and incompletely integrated into clinical decision-making. This narrative review synthesizes data from human CP cohorts and complementary experimental models to summarize inflammatory, neuropathic, and metabolic drivers of pancreatitis-associated pain and to evaluate how integrated multi-omics approaches may enable mechanism-based precision management. Current treatment relies on lifestyle modification, anatomy-guided interventions, stepwise pharmacologic escalation, and surgery for refractory cases. Emerging ion-channel-targeted therapies show promise, but inconsistent patient selection and limited biomarker guidance constrain therapeutic precision. FINDINGS: CP-associated pain arises from convergent inflammatory, neuroimmune, neuropathic, and metabolic pathways that promote peripheral and central sensitization with sustained neuroplastic remodeling. Advances in clinical phenotyping have improved characterization of pain subtypes; however, integration of biologic data remains limited. Genetic association studies increasingly implicate pathways linked to severe or persistent pain phenotypes. Omics investigations have identified candidate genomic, proteomic, and metabolomic signals that may support biologically informed stratification and treatment prediction. Nevertheless, most studies are cross-sectional, modality-specific, and derived from heterogeneous cohorts with inconsistent endpoints and limited external validation. CONCLUSIONS: Integration of rigorous clinical phenotyping with longitudinal, multi-omics modeling provides a framework for developing testable, mechanism-based biomarkers to guide personalized analgesic and procedural strategies while supporting opioid-sparing care. Priorities include harmonization of multicenter datasets, standardized and longitudinal pain outcome measurement, expanded paired biospecimen collection, and external validation of predictive models. Such efforts may enable biologically grounded pain stratification and facilitate translation of biomarker-guided decision tools into routine clinical practice.
Suppression of Nr1d1/Bnip3-dependent mitophagy by notch signaling aggravates inflammatory response in RSV-infected mice lungs.
Lei Y, Liu Z, Du H … +5 more , Zhang R, Hu H, Yang P, Zheng J, Zhao D
Inflamm Res · 2026 Apr · PMID 41961300 · Publisher ↗
BACKGROUND: Alveolar macrophages (AMs) are crucial for defending against respiratory syncytial virus (RSV) and regulating lung inflammation. Notch signaling is essential for macrophage polarization and its functional div...
BACKGROUND: Alveolar macrophages (AMs) are crucial for defending against respiratory syncytial virus (RSV) and regulating lung inflammation. Notch signaling is essential for macrophage polarization and its functional diversity.However, the role of macrophages Notch1 in RSV-induced lung injury and its underlying mechanisms remain incompletely understood. METHODS: This study used macrophage-specific Notch1 knockout (MKO) mice to investigate the lung lesions and inflammation in RSV-infected mice. The effects of various interventions, including JAG1, Nr1d1 inhibitor, and Bnip3 gene manipulation, were assessed in RSV-infected mice. Western blot (WB) was used to measure the expression of inflammasome-related proteins, such as NLR family, pyrin domain containing 3 (Nlrp3), Asc, Cleaved-caspase1, and nuclear receptor subfamily 1, group D, member 1 (Nr1d1), BCL2/adenovirus E1B 19 kDa interacting protein 3 (Bnip3) in lung or macrophages. Additionally, RNA sequencing (RNA-seq) of macrophages from RSV-infected mice was performed to identify differential gene expression between MKO and wild-type (Flox) mice. Confocal microscopy visualized the localization of autophagy complexes in cellular mitochondria. ELISA assays measured LDH, IL-1β and IL-18 levels in bronchoalveolar lavage fluid (BALF). RESULTS: Compared to Flox mice, MKO mice showed milder lung lesions, increased Nr1d1 and Bnip3 expression, and decreased Nlrp3 inflammasome activity in RSV-exposed mice. Moreover, Nr1d1 inhibitor reduced Bnip3 expression, increased IL-1β and IL-18 release, and exacerbated pulmonary inflammation. Inhibiting Bnip3 exacerbated RSV-induced lung injury by enhancing Nlrp3 inflammasome activity and impairing mitophagy. CONCLUSION: These results suggest that Notch signaling regulates Nr1d1/Bnip3-induced mitophagy, influencing the Nlrp3 inflammasome and the inflammatory response during RSV infection.
B cell-driven immune remodeling in inflammatory bowel disease: links to pathogenesis and therapeutic failure.
Li G, Cao H, Hong J
Inflamm Res · 2026 Apr · PMID 41961250 · Publisher ↗
OBJECTIVE: Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder characterized by dysregulated intestinal immune responses. Accumulating evidence indicates that B-lineage cells play important roles in sh...
OBJECTIVE: Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder characterized by dysregulated intestinal immune responses. Accumulating evidence indicates that B-lineage cells play important roles in shaping mucosal immunity. This review aims to summarize the physiological and pathological roles of intestinal B-lineage cells in IBD, with a particular focus on their functional remodeling during biologic therapy and emerging strategies to overcome biologic resistance. METHODS: Relevant literature on B-lineage cells, IBD, mucosal immunity, and biologic therapies was searched and reviewed. RESULTS: Under physiological conditions, plasmablasts and plasma cells maintain intestinal homeostasis through IgA secretion, whereas B lymphocytes contribute via cytokine production, antigen presentation, and cellular interactions that support epithelial repair and barrier integrity. In IBD, B-lineage cells undergo pathogenic remodeling, with expanded effector subsets exhibiting enhanced inflammatory cytokine production, altered antibody profiles, and increased interactions with T cells, myeloid cells, and stromal cells. These changes disrupt epithelial integrity and sustain maladaptive immune activation, contributing to chronic mucosal inflammation. Biologic therapies targeting TNF, α4β7 integrin, and IL-12/23 exert direct and indirect effects on B-lineage cells, modulating their trafficking, survival, and functional states, and partially restoring immune balance. Nevertheless, persistent cellular plasticity and dysregulated survival signaling may enable pathogenic B-lineage subsets to retain inflammatory potential, contributing to treatment non-response or secondary loss of efficacy. CONCLUSION: B-lineage cells play critical roles in both intestinal homeostasis and IBD pathogenesis. Understanding their functional remodeling during biologic therapy may provide insights into treatment resistance and inform emerging strategies to overcome biologic resistance in IBD.
Metabolite sensing receptors in macrophage reprogramming: from inflammation to resolution.
Rai SK, Gupta S, Sarangi PP
Inflamm Res · 2026 Apr · PMID 41961107 · Publisher ↗
BACKGROUND: Macrophages are central to innate immunity, orchestrating both the inflammatory and resolution phases of host defense. Emerging evidence indicates that immunometabolic crosstalk critically dictates macrophage...
BACKGROUND: Macrophages are central to innate immunity, orchestrating both the inflammatory and resolution phases of host defense. Emerging evidence indicates that immunometabolic crosstalk critically dictates macrophage polarization and functions. Disruptions in cellular metabolism can impair these regulatory mechanisms, leading to dysfunctional immune responses associated with various disease pathologies. A key aspect of this regulation involves metabolite-sensing receptors that detect changes in intracellular metabolic intermediates and in extracellular metabolites derived from the diet, host tissues, and the microbiome. METHODS: We have conducted a literature review of original research and review articles on metabolite-sensing receptors and their roles in immune cell function, drawn from central databases including PubMed and Google Scholar. RESULTS AND CONCLUSION: A major class of extracellular metabolite-sensing receptors is G-protein-coupled receptors (GPCRs), which can directly or indirectly modulate macrophage activation, migration, cytokine production, and metabolic reprogramming. By fine-tuning macrophage-specific functions, metabolite-sensing receptors act as critical regulatory nodes in both inflammation and immune homeostasis, beyond their canonical role in sensing metabolic cues. This review provides a comprehensive overview of the metabolite-sensing receptor interactome, highlighting their central role in macrophage biology and underscoring their potential as therapeutic targets in inflammatory and metabolic diseases.
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