Inflammation Research[JOURNAL]
Sun
200 papers
KIAA1429 as a therapeutic target in osteosarcoma: challenging the linear ferroptosis pathway and evaluating translational hurdles.
Yang D, Yu L, Ye Z … +1 more , Wang G
Inflamm Res · 2025 Dec · PMID 41441982 · Publisher ↗
The recent proposal by Xie et al. that KIAA1429 silencing ameliorates osteosarcoma progression primarily by promoting ferroptosis via the Nrf2/NQO1 axis offers a valuable yet potentially oversimplified mechanistic model....
The recent proposal by Xie et al. that KIAA1429 silencing ameliorates osteosarcoma progression primarily by promoting ferroptosis via the Nrf2/NQO1 axis offers a valuable yet potentially oversimplified mechanistic model. While this finding underscores the significant link between the m6A writer KIAA1429 and redox homeostasis, our critical appraisal identifies several conceptual oversights that challenge the directness and exclusivity of this pathway. The core vulnerability lies in attributing the complex phenotypic outcome of silencing a global RNA modifier to a single downstream axis, without conclusive genetic rescue evidence to establish Nrf2's indispensable role. Moreover, the pleiotropic nature of KIAA1429, which regulates a vast transcriptome encompassing other key ferroptosis regulators (e.g., GPX4, SLC7A11), is largely overlooked. The translational potential of targeting KIAA1429 is further questioned by the lack of assessment regarding on-target toxicities in normal cells, such as osteoblasts and mesenchymal stem cells, and the foreseeable resistance mechanisms via functional redundancy within the m6A machinery. This commentary urges a more nuanced interpretation of the data and highlights the formidable pharmacological challenges that must be overcome before KIAA1429 can be considered a viable therapeutic target.
Novel insights into asthma pathophysiology and pharmacological interventions: spiral of respiratory symptoms and psychiatric episodes.
Nakagawa Y, Yamada S
Inflamm Res · 2025 Dec · PMID 41441880 · Publisher ↗
BACKGROUND: Asthma is the most common respiratory disorder with airway inflammation and alterations. Included among comorbidities with asthma are psychiatric conditions; however, it is unclear how these disorders engagin...
BACKGROUND: Asthma is the most common respiratory disorder with airway inflammation and alterations. Included among comorbidities with asthma are psychiatric conditions; however, it is unclear how these disorders engaging with each other. FINDINGS: In type-2-high asthma, allergens cause airway type-2 immune responses with respiratory symptoms. When the patients experience high blood levels of pro-inflammatory cytokines, they can promote reactive glial cell-induced neuroinflammation and hyperactivation of the thalamus, insula, and cingulate cortex, responsible for interoceptive states, as well as those of the hippocampus/amygdala, contributing to emotions, via the blood-cerebrospinal fluid barrier structure and cerebrospinal fluid system. The prefrontal cortex controls these brain regions to maintain cognitive responses in harmony with interoception and emotion, while over time, dysregulation of the prefrontal cortex is induced. This likely prompts cognitive-perceptual bias-related cognitive distortion or catastrophic thinking of respiratory symptoms and asthma-dependent emotions, which, rather than airway sensory hyperinnervation, may mediate uncontrollable respiratory sensory perception, leading to a spiral along with asthma symptoms. CONCLUSION: Collectively, it is hypothesized that type-2 immune responses initiate airway abnormalities, while neuroinflammation and neuronal hyperactivation can induce brain neural network disruption with psychiatric episodes, presumably enhancing the progression of asthma. The notion predicts novel therapeutics for type-2-high asthma comorbid with psychiatric disorders.
Mechano-metabolic dysregulation in osteoarthritis: Piezo1-mediated mitophagy impairment as a novel therapeutic target.
Yang D, Yang L, Yang W … +4 more , Chen J, Wang S, Yang J, Wang G
Inflamm Res · 2025 Dec · PMID 41410756 · Publisher ↗
The recent study by Yu et al. (2025) elucidates a critical mechanism linking mechanical stress to mitochondrial dysfunction in osteoarthritis (OA), demonstrating that Piezo1 activation is associated with impaired PINK1/P...
The recent study by Yu et al. (2025) elucidates a critical mechanism linking mechanical stress to mitochondrial dysfunction in osteoarthritis (OA), demonstrating that Piezo1 activation is associated with impaired PINK1/Parkin-mediated mitophagy, leading to chondrocyte injury and cartilage degradation. While this work significantly advances our understanding of OA pathogenesis by integrating biomechanical and bioenergetic perspectives, key aspects require further exploration. Specifically, the downstream signaling mechanisms mediated by calcium influx, the potential role of reactive oxygen species (ROS) and inflammasome activation, and alternative therapeutic strategies beyond Piezo1 inhibition warrant deeper investigation. This commentary highlights these avenues for future research and emphasizes the importance of targeting mitochondrial quality control as a promising approach for OA therapy.
TREM2-driven peripheral macrophage regulation in inflammatory diseases: implications extending beyond neurological disorders.
Zhou X, Liu Z, Li S … +4 more , Yu S, Sun M, Si Z, Zhu W
Inflamm Res · 2025 Dec · PMID 41408002 · Publisher ↗
Triggering receptor expressed on myeloid cells 2 (TREM2), a crucial immunomodulatory receptor expressed on myeloid cells, is pivotal in regulating immune responses and maintaining tissue homeostasis. TREM2 has gained pro...
Triggering receptor expressed on myeloid cells 2 (TREM2), a crucial immunomodulatory receptor expressed on myeloid cells, is pivotal in regulating immune responses and maintaining tissue homeostasis. TREM2 has gained prominence as a key factor in deciphering the pathological mechanisms of diverse diseases, particularly due to its significant influence on macrophage function in disease progression. The TREM2 signaling pathway governs macrophage activation, polarization, phagocytosis, and cytokine secretion, thereby impacting immune regulation and the progression of inflammation. Dysregulation of TREM2-mediated macrophage function is closely linked to the pathogenesis of multiple systemic diseases. Specifically, in the central nervous system, extensive research has focused on TREM2's regulatory influence on microglial function. Concurrently, its pathogenic roles in disorders beyond the neurological spectrum have increasingly garnered investigative attention. This review offers a structured overview of recent advances in understanding the mechanisms through which TREM2 regulates macrophage function and its implications in non-neurological diseases. Particular emphasis is placed on the potential of TREM2 as a therapeutic target for modulating macrophage-mediated pathological processes.
Target Fibroblast-B cell crosstalk via MIF signaling drives pathogenic B cell differentiation and joint damage in knee osteoarthritis.
Tu B, Zhu Z, Li Y … +8 more , Zhu Z, Wang S, Lu P, Li Y, Yang S, Hu D, Fang R, Ning R
Inflamm Res · 2025 Dec · PMID 41407905 · Publisher ↗
BACKGROUND: B cells play a critical role in knee osteoarthritis (KOA), however, the heterogeneity, activation mechanisms, and their contribution to cartilage damage in KOA joints are still not fully understood. METHODS:...
BACKGROUND: B cells play a critical role in knee osteoarthritis (KOA), however, the heterogeneity, activation mechanisms, and their contribution to cartilage damage in KOA joints are still not fully understood. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on joint tissues from 9 healthy controls and 21 KOA patients, integrating transcriptomic profiling, pseudotime trajectory analysis, and ligand-receptor interaction mapping. Key findings were validated using immunohistochemistry, Western blotting, in vitro co-culture systems, and a murine KOA model induced by anterior cruciate ligament transection and destabilization of the medial meniscus (ACLT + DMM). RESULTS: scRNA-seq analysis identified 31 cell clusters, with B cells showing marked enrichment in subchondral bone and synovium of KOA joints, particularly in older and female patients. Re-clustering of B cells revealed eight distinct subgroups, including pathogenic DERL3 and CD79BB cell, which exhibited tissue-specific localization and stage-specific expansion during KOA progression. Pseudotime and regulon analyses highlighted JUN as a key transcription factor driving DERL3 B cell differentiation. Fibroblasts emerged as critical regulators of B cell activation via MIF-(CD74 + CXCR4/CD44) signaling. Mechanistically, IL-1β-stimulated fibroblasts secreted MIF, inducing DERL3 expression in naïve B cells and may contribute to chondrocyte catabolic responses (increased MMP13, decreased COL2). Pharmacological inhibition of MIF reversed these effects in vitro and awas associated with reduced joint degeneration and improved gait and bone microarchitecture in KOA mice. CONCLUSION: This study unveils a fibroblast-B cell crosstalk axis mediated by MIF signaling in KOA pathogenesis. Targeting MIF signaling may represent a promising therapeutic strategy to mitigate B cell-associated joint inflammation and structural alterations in KOA.
Genetic mechanisms of pollinosis: interactions between genes and environmental factors.
Yang F, Zheng J, Gao M … +1 more , Ning L
Inflamm Res · 2025 Dec · PMID 41372550 · Publisher ↗
BACKGROUND: Pollinosis, or pollen-induced allergic rhinitis, results from complex interactions among genetic susceptibility, environmental exposures, and epigenetic regulation. Risk variants within Th2 signaling and IgE...
BACKGROUND: Pollinosis, or pollen-induced allergic rhinitis, results from complex interactions among genetic susceptibility, environmental exposures, and epigenetic regulation. Risk variants within Th2 signaling and IgE regulatory pathways (e.g., IL13, IL4R, ADAM33) have been identified, while genome-wide association and transcriptomic analyses implicate additional genes involved in immune regulation and epithelial barrier integrity. Environmental factors such as urbanization, pollen burden, and air pollution further amplify disease risk, partly through epigenetic modifications. METHODS: This narrative review synthesizes evidence from candidate-gene studies, genome-wide association studies (GWAS), transcriptomic datasets, and epigenetic investigations, with particular emphasis on gene-environment interactions in pollen-induced allergic rhinitis. We highlight replicated findings, compare results across study designs and populations, and critically appraise the strength of evidence and methodological limitations. RESULTS: Convergent data support the contribution of Th2-related and IgE-regulatory loci, alongside additional GWAS-implicated genes, to pollinosis susceptibility. Transcriptomic and epigenomic studies reveal dysregulated immune pathways and environmentally induced DNA methylation and chromatin changes. However, replication across ancestries is limited, variant-to-function mechanisms remain incompletely defined, and current polygenic risk scores explain only a modest proportion of disease variance. Integration of environmental metrics such as pollen load and air pollution into genetic and epigenetic models is still at an early stage. CONCLUSIONS: Bridging molecular discoveries with environmental and clinical contexts is essential to advance precision prevention and personalized management of pollinosis. Future work should focus on fine-mapping with tissue-specific colocalization, seasonal single-cell multi-omics, and quantitative models that combine genetic risk with real-time exposure data. Clinically, polygenic risk stratification and individualized immunotherapy hold promise, but their predictive performance, feasibility, and cost-effectiveness require validation in large, ancestrally diverse cohorts.
Effects of curcumin and Curcuma longa extract on inflammatory biomarkers in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE): a systematic review and meta-analysis of randomized controlled trials.
Liu AJ, Wu PC, Chen YP … +2 more , Chu HT, Chang HH
Inflamm Res · 2025 Dec · PMID 41372521 · Full text
BACKGROUND: Curcumin and Curcuma longa extract have been proposed as adjunct therapies for autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) due to their anti-inflammatory and i...
BACKGROUND: Curcumin and Curcuma longa extract have been proposed as adjunct therapies for autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) due to their anti-inflammatory and immunomodulatory properties. The purpose of this study was to determine the effects of curcumin and Curcuma longa extract on inflammatory biomarkers in patients with RA and SLE. METHODS: PubMed, EMBASE, and Cochrane CENTRAL databases were searched to May 14, 2025. Randomized controlled trials (RCTs) comparing curcumin or Curcuma longa extract with placebo or standard therapy in patients with RA or SLE were included. The primary outcomes were changes in disease activity score (DAS-28), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level analyzed using standardized mean differences (SMDs) with a random-effects model. Heterogeneity was assessed using the I statistic, and sensitivity analyses were conducted using a leave-one-out approach. RESULTS: Seven RCTs involving 314 patients were included. The meta-analysis revealed no significant effect of curcumin or Curcuma longa extract on DAS-28 (pooled SMD = - 2.34, 95% confidence level [CI]: - 5.13 to 0.44; I = 96.0%), ESR (pooled SMD = - 1.49, 95% CI - 3.71 to 0.72; I = 91.7%), or CRP (pooled SMD = - 1.65, 95% CI - 3.88 to 0.58; I = 91.6%). Substantial heterogeneity was observed across all outcomes. CONCLUSIONS: This meta-analysis suggests that curcumin and Curcuma longa extract have limited and inconsistent effects on inflammatory biomarkers in patients with RA and SLE. Larger, well-designed RCTs are needed to clarify their clinical utility as adjunct therapies.
LncRNA TYMSOS stimulates immune escape and the advancement of cervical squamous cell carcinoma by regulating miR-134-5p/KRAS expression.
Zhang Q, Tang H, Shen W … +3 more , Gao J, Zhang B, Ying C
Inflamm Res · 2025 Dec · PMID 41372482 · Publisher ↗
BACKGROUND: LncRNAs can regulate related miRNAs and participate in the regulation of tumorigenesis, progression, and immune escape in tumors. AIM: To examine the clinical and functional impact of lncRNA TYMSOS in the adv...
BACKGROUND: LncRNAs can regulate related miRNAs and participate in the regulation of tumorigenesis, progression, and immune escape in tumors. AIM: To examine the clinical and functional impact of lncRNA TYMSOS in the advancement and immune escape of cervical cancer. METHODS: The abundances of TYMSOS in cervical squamous cell carcinoma (CSCC) patients were detected using RT-qPCR and verified by bioinformatic analysis. The functional impact of TYMSOS in cervical cancer cells was assessed by CCK-8 and Transwell assays. ELISA assay was utilized to determine the amounts of IFN-γ and TNF-α released. The CytoTox 96 non-radioactive cytotoxicity assay was conducted to measure the cytotoxicity of NK92 cells against cervical cancer cells. The interaction among TYMSOS, miR-134-5p, and KRAS was assessed by dual-luciferase reporter assay, RNA pull-down, and RIP assays. RESULTS: TYMSOS and KRAS were upregulated while miR-134-5p was decreased in CSCC patients. Serum TYMSOS levels had predictive value for CSCC patients and tumor tissue TYMSOS had prognostic value in predicting progression-free survival. Silencing TYMSOS repressed cell proliferation, migration, and invasion abilities, while enhancing the cytotoxic activity of NK cells against cervical cancer cells and stimulated the release of IFN-γ and TNF-α. miR-134-5p was a target of TYMSOS and KRAS was a potential target of miR-134-5p. Interference of KRAS abolished the effects of miR-134-5p on the malignant behaviors and killing influence of NK92 cells to cervical cancer cells. CONCLUSION: Increased TYMSOS was linked to adverse prognosis, malignant progression, and immune escape in cervical cancer by modulating miR-134-5p/KRAS axis.
Kinin receptors in adipose tissue: drivers of inflammation and metabolic dysfunction in obesity.
Cárdenas-Oyarzo A, Armijo C, Salazar M … +4 more , Villarroel P, Catalán M, Rojas-Mancilla E, Ehrenfeld P
Inflamm Res · 2025 Dec · PMID 41345311 · Publisher ↗
BACKGROUND: Kinins, bioactive peptides produced through the proteolytic activity of kallikrein1, are members of the kallikrein-kinin system (KKS) and play crucial roles in regulating physiological processes such as infla...
BACKGROUND: Kinins, bioactive peptides produced through the proteolytic activity of kallikrein1, are members of the kallikrein-kinin system (KKS) and play crucial roles in regulating physiological processes such as inflammation, blood pressure, vascular permeability, and cell function and growth. In adipose tissue, bradykinin (BK) and des-Arg9-BK (DBK), produced by plasma kallikrein (KLKB1), act via their receptors B2 (B2R) and B1 (B1R), respectively. B1R predominates in preadipocytes, while B2R is expressed during adipogenesis, likely driving adipose tissue expansion and sustaining chronic low-grade inflammation, both hallmarks of obesity and its associated metabolic disorders. Obesity, a multifactorial metabolic disease, is closely linked to adipose tissue dysfunction. This dysfunction is driven by inflammation and oxidative stress, which in turn alter adipogenesis, lipolysis, and insulin and leptin signaling, contributing to obesity and its comorbidities. PURPOSE: This review focuses on the role of the KKS in adipose tissue homeostasis and function. FINDINGS: Evidence from animal models suggests that B1R ablation or antagonism results in a healthier phenotype, characterized by improved leptin and insulin sensitivity, increased lipid oxidation, reduced adipose hypertrophy, and diminished production of proinflammatory mediators and reactive oxygen species. Conversely, B2R activation may exert protective effects by enhancing insulin signaling and promoting glucose uptake, although its role remains incompletely understood and appears context-dependent. CONCLUSION: The KKS proposes it as a promising therapeutic target, biomarker, and prognostic indicator in anti-obesity pharmacological strategies.
Therapeutic effect of an MRGPRX2/MRGPRB2 antagonist on LL-37-induced rosacea-like inflammation in mice.
Chow BKC, Choi YG, Wong TK … +3 more , Nawabjan SA, Li K, Kumar M
Inflamm Res · 2025 Nov · PMID 41296102 · Full text
INTRODUCTION: Rosacea is a chronic inflammatory skin disorder characterized by symptoms like itching, redness, and impaired skin barrier function. Mast cell activation plays a crucial role in its pathogenesis. Recent evi...
INTRODUCTION: Rosacea is a chronic inflammatory skin disorder characterized by symptoms like itching, redness, and impaired skin barrier function. Mast cell activation plays a crucial role in its pathogenesis. Recent evidence shows higher expression of mast cell receptor MRGPRX2/MRGPRB2 in rosacea patients' skin tissues and its potential as a novel drug target. We evaluated the therapeutic effect of a novel small-molecule MRGPRX2/MRGPRB2 antagonist in a mouse model of rosacea and itch. METHODS: The therapeutic effects of GE1111 were evaluated in vivo on wildtype and MRGPRB2 knock-out mice with LL-37-induced rosacea. Serum MCP-1 level and histochemistry measured inflammation and mast cell degranulation in skin tissue. Functional in vitro cell culture assays were developed using MRGPRX2/MRGPRB2 agonist LL-37, mast cells, keratinocytes, and macrophage cell lines. RESULTS: LL-37-treated mice showed redness, increased serum MCP-1, and epidermal thickness of skin tissue, while these changes were absent in LL-37-treated MRGPRB2 knock-out mice. Treatment with GE1111 reduced rosacea symptoms, epidermal thickness, and serum MCP-1 levels. GE1111 protected tight junction protein expression and reduced mast cell degranulation and inflammatory cytokine gene and protein expression in skin lesions. GE1111 treatment reduced the number and duration of itch in the compound 48/80 induced itch model. In vitro evidence showed GE1111's mechanism by inhibiting inflammatory interaction of mast cells with keratinocytes and macrophages. CONCLUSION: GE1111 showed promising therapeutic effects in rosacea via targeting interactions between mast cells, keratinocytes, and macrophages and inhibiting inflammatory cytokines. These findings open possibilities for developing MRGPRX2/MRGPRB2 antagonists as novel treatments for rosacea.
Angiotensin-(1-7) treatment improves pneumonia and prevents sepsis caused by pneumococcal infection.
Melo EM, Galvão I, Felix FB … +8 more , Magalhães FMV, Rago F, Machado MG, Ascenção FR, Campagnole-Santos MJ, Dos Santos RAS, Cassali GD, Teixeira MM
Inflamm Res · 2025 Nov · PMID 41296084 · Publisher ↗
BACKGROUND: Pneumonia caused by Streptococcus pneumoniae remains a major global health concern, leading to significant morbidity and mortality. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide with known anti-infla...
BACKGROUND: Pneumonia caused by Streptococcus pneumoniae remains a major global health concern, leading to significant morbidity and mortality. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide with known anti-inflammatory and pro-resolving properties, but its therapeutic potential in bacterial pneumonia is not fully understood. PURPOSE: This study aimed to investigate whether Ang-(1-7) could reduce inflammation, improve bacterial clearance, and enhance survival in a murine model of pneumococcal pneumonia, alone or in combination with the antibiotic ceftriaxone. METHODS: A mouse model of S. pneumoniae pneumonia was used to evaluate the effects of Ang-(1-7). Mice received Ang-(1-7) treatment after infection, either alone or combined with ceftriaxone. Outcomes included leukocyte infiltration, pulmonary edema, lung tissue damage, cytokine production (TNF-α, IL-6, CXCL-1), bacterial load in bronchoalveolar lavage and blood, survival analysis, bone marrow-derived macrophage phagocytosis assays, and expression of lung barrier-associated genes. RESULTS: Ang-(1-7) reduced leukocyte infiltration, pulmonary edema, and lung tissue injury, and decreased pro-inflammatory cytokine levels. Treatment improved bacterial clearance in both lungs and bloodstream and increased survival in infected mice. Importantly, combining Ang-(1-7) with ceftriaxone further enhanced survival, even when treatment initiation was delayed. Mechanistically, Ang-(1-7) increased macrophage phagocytic activity and upregulated genes associated with lung barrier integrity. CONCLUSION: Ang-(1-7) decreased inflammation, improved bacterial clearance, and enhanced survival in severe pneumococcal pneumonia. Its combination with ceftriaxone produced additive benefits, supporting Ang-(1-7) as a promising adjuvant therapeutic strategy in this infectious condition.
Sepsis and heatstroke: overlapping and distinct mechanisms of systemic inflammation.
Iba T, Helms J, Nagaoka I … +3 more , Kondo Y, Ferrer R, Levy JH
Inflamm Res · 2025 Nov · PMID 41296074 · Publisher ↗
BACKGROUND: Sepsis and heatstroke, although arising from microbial infection or environmental heat exposure, converge upon similar pathophysiological systemic inflammatory responses that include immune dysregulation, mit...
BACKGROUND: Sepsis and heatstroke, although arising from microbial infection or environmental heat exposure, converge upon similar pathophysiological systemic inflammatory responses that include immune dysregulation, mitochondrial dysfunction, endothelial injury, and multiorgan failure. Despite this overlap, important mechanistic differences, especially in the initiating triggers and immune response dynamics, distinguish their clinical manifestations and therapeutic strategies. FINDINGS: Sepsis is initiated by pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptors, whereas heatstroke stems from the release of damage-associated molecular patterns (DAMPs) in response to thermal injury. Both syndromes disrupt mitochondrial integrity, leading to impaired oxidative phosphorylation, an excess production of reactive oxygen species (ROS), and the release of mitochondrial DNA and cytochrome C, which further amplify inflammation and promote cell death. Leukocytes undergo diverse forms of death-including apoptosis, necroptosis, pyroptosis, and ferroptosis-compounding immune dysfunction. Coagulopathy and disseminated intravascular coagulation are prevalent in both conditions, driven by endothelial injury, platelet activation, and NET formation, although microbial toxins intensify this response in sepsis. CONCLUSIONS: This review synthesizes current evidence to delineate the converging and diverging pathways of sepsis and heatstroke, with a focus on mitochondrial injury, immune paralysis, and thromboinflammation. We also explore emerging biomarkers and novel therapeutic targets, including mitochondrial stabilizers and modulators of cell death. A comprehensive understanding of these mechanisms can inform precision medicine strategies and improve outcomes in both syndromes.
Dexamethasone regulates gene expression in chondrocytes through MKP-1 and downregulates cholesterol hydroxylases CH25H and CYP7B1.
Lehtola T, Pemmari A, Nummenmaa E … +5 more , Valjus I, Hämäläinen M, Moilanen T, Vuolteenaho K, Moilanen E
Inflamm Res · 2025 Nov · PMID 41296055 · Full text
OBJECTIVE: Mitogen-activated protein kinase phosphatase-1 (MKP-1) is an anti-inflammatory enzyme whose expression is increased by glucocorticoids (GCs). MKP-1 dephosphorylates and thereby inactivates mitogen-activated pr...
OBJECTIVE: Mitogen-activated protein kinase phosphatase-1 (MKP-1) is an anti-inflammatory enzyme whose expression is increased by glucocorticoids (GCs). MKP-1 dephosphorylates and thereby inactivates mitogen-activated protein kinases (MAP kinases) which are major signaling pathways mediating proinflammatory effects of various extracellular factors to gene expression. In this study, we examined the regulatory effects of the synthetic glucocorticoid dexamethasone on the expression of a panel of genes previously identified as the top 15 critical mediators in the pathogenesis of osteoarthritis (OA). Furthermore, we investigated the hypothesis that MKP-1 is involved in mediating these glucocorticoid-induced effects in chondrocytes. METHODS: The effects of dexamethasone on the interleukin-1β-induced expression of OA target genes were investigated with RNA-seq and quantitative RT-PCR in primary cultured chondrocytes from wild-type and MKP-1 deficient mice, and from OA patients undergoing joint replacement surgery. RESULTS: Under these conditions, dexamethasone was found to significantly alter the expression of seven out of the 15 OA-related genes including two cholesterol hydroxylases, namely cholesterol 25-hydroxylase (CH25H) and 25-hydroxycholesterol 7-hydroxylase (also known as cytochrome P450 family 7 subfamily B member 1, CYP7B1). Dexamethasone attenuated the interleukin-1β -induced expression of CH25H and CYP7B1 in primary chondrocytes of wild-type mice and in primary human OA chondrocytes, but the dexamethasone effect was absent (CYP7B1) or reduced (CH25H) in chondrocytes from MKP-1 deficient mice. Furthermore, the p38 MAP kinase inhibitor BIRB796 significantly inhibited CH25H expression while the JNK MAP kinase inhibitor SP600125 attenuated CYP7B1 expression in human OA chondrocytes. CONCLUSIONS: In conjunction with previous findings, the current data substantiate the role of MKP-1 as a protective factor in chondrocytes and highlight its potential as a therapeutic target for the treatment of osteoarthritis, because increased levels of cholesterol and its metabolism by CH25H and CYP7B1 are involved in the pathogenesis of OA, particularly in its obesity-associated phenotype.
Myeloid-specific tristetraprolin mitigates postsurgical incisional pain by suppressing proinflammatory responses.
Guha A, Sorge RE, Si Y … +7 more , Smith R, Baig SM, Husain MA, Totsch SK, Piper AM, Blackshear PJ, King PH
Inflamm Res · 2025 Nov · PMID 41296045 · Full text
BACKGROUND: Proinflammatory mediators including COX-2, IL-1β, IL-6, and TNF-α, play major roles in the initiation of postsurgical pain. Produced primarily by activated macrophages and microglia, these mediators drive hyp...
BACKGROUND: Proinflammatory mediators including COX-2, IL-1β, IL-6, and TNF-α, play major roles in the initiation of postsurgical pain. Produced primarily by activated macrophages and microglia, these mediators drive hyperexcitation of nociceptors and promote peripheral and central pain sensitization. Post-transcriptional RNA regulation is a major control point for these mediators, centering around adenine- and uridine-rich elements (ARE) in the 3' untranslated regions of their mRNA transcripts. The ARE governs RNA stability and translational efficiency through an interaction with ARE-specific RNA binding proteins (AUBP). Tristetraprolin (TTP) is an AUBP that promotes RNA degradation and translational silencing of these mediators to suppress inflammatory responses. METHODS: Mice with myeloid-specific TTP knockout or TTP knock-in underwent paw incision and were assessed for mechanical allodynia and thermal sensitivity. Molecular and cellular inflammatory responses were monitored at the site of incision, dorsal root ganglia (DRG) and lumbar spinal cord (L-SC) by qPCR, ELISA, immunohistochemistry and/or flow cytometry. RESULTS: TTP deletion exacerbated post-incisional allodynic pain in parallel with increased edema at the site of injury and delayed wound healing but without significant effects on thermal sensitivity. There was an increase in infiltrating macrophages at the incisional site, particularly at the dermal-epidermal junction, in parallel with a robust increase in proinflammatory/pronociceptive mediators. An enhanced inflammatory response was also detected in the circulation, ipsilateral DRG and L-SC which persisted through post-incisional day 7. Conversely, TTP knock-in mice showed attenuation of allodynic pain and inflammatory responses in skin, DRG, L-SC, and circulation. CONCLUSION: TTP plays a critical role in mitigating postsurgical pain by tamping down peripheral, central and systemic inflammatory responses, thus identifying a new target and mechanism for future development of pain therapeutics.
Commentary on "CircMAPK1 induces cell pyroptosis in sepsis-induced lung injury by mediating KDM2B mRNA decay to epigenetically regulate WNK1".
Bai WJ, Li CG
Inflamm Res · 2025 Nov · PMID 41296023 · Full text
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Differential regulation of 5-lipoxygenase and leukotriene-C4-synthase expression by IFNγ, IL-4 and IL-13 in human monocytes and macrophages from patients with atopic dermatitis.
Lietzau S, Traidl S, Riesselmann C … +2 more , Werfel T, Mommert S
Inflamm Res · 2025 Nov · PMID 41296013 · Full text
INTRODUCTION: Skin lesions in atopic dermatitis (AD) are characterized by elevated levels of both Th1 and Th2 cytokines, along with increased concentrations of inflammatory mediators such as cysteinyl leukotrienes (CysLT...
INTRODUCTION: Skin lesions in atopic dermatitis (AD) are characterized by elevated levels of both Th1 and Th2 cytokines, along with increased concentrations of inflammatory mediators such as cysteinyl leukotrienes (CysLTs). The enzymes 5-lipoxygenase (5-LO/ALOX5) and leukotriene-C4-synthase (LTC4S), which are essential in CysLT biosynthesis, are highly expressed by macrophages. We aimed to investigate the expression of 5-LO/ALOX5 and LTC4S mRNA in lesional AD skin at single cell level. Furthermore, we analyzed the regulatory effects of the Th1 cytokine interferon gamma (IFNγ) and the Th2 cytokines IL-4, IL-13 on 5-LO/ALOX5 and LTC4S expression in monocytes and macrophages derived from AD patients and healthy volunteers. METHODS: Single-cell RNA sequencing (scRNA-seq) data from lesional AD skin biopsies, as reported in a previously published study, were re-analyzed to evaluate 5-LO/ALOX5 and LTC4S mRNA expression. PBMCs from AD patients, healthy volunteers and anonymous donors were used to isolate monocytes. Macrophages were generated in the presence of GM-CSF or M-CSF for 10 days. Cells were stimulated with IFNγ, IL-4 or IL-13. 5-LO/ALOX5 and LTC4S mRNA expressions were quantified by q-PCR. Intracellular 5-LO/ALOX5 expression was assessed by immunocytochemistry. RESULTS: Re-analysis of scRNA-seq data revealed high levels of 5-LO/ALOX5 and LTC4S transcripts in monocytes and macrophages. In-vitro, IFNγ induced 5-LO/ALOX5 mRNA expression in blood derived monocytes and macrophages from AD patients, and protein levels in both monocytes and macrophages from anonymous donors, whereas IL-4 and IL-13 suppressed its expression. Vice versa LTC4S mRNA expression was downregulated by IFNγ but upregulated by IL-13. Higher baseline mRNA expressions of 5-LO/ALOX5 and LTC4S were observed in blood derived monocytes from AD patients compared to cells from healthy volunteers . CONCLUSION: We demonstrate that IFNγ enhances the 5-LO/ALOX5-catalyzed stage of CysLT synthesis, whereas IL-13 promotes the LTC4S dependent pathway in human monocytes or macrophages. These findings suggest a potential role for these cells in driving CysLT production in acute and chronic AD lesions and may give rise for future therapeutic interventions targeting this pathway.
The potential role of GLP-1 receptor agonists in the management of psoriatic disease: a scoping review.
Buonanno S, Gaggiano C, Terribili R … +3 more , Cantarini L, Frediani B, Gentileschi S
Inflamm Res · 2025 Nov · PMID 41266905 · Full text
BACKGROUND: Psoriatic disease (PsD) is a chronic systemic inflammatory condition associated with significant cardiometabolic comorbidities, including obesity, type 2 diabetes mellitus (T2DM), and cardiovascular (CV) dise...
BACKGROUND: Psoriatic disease (PsD) is a chronic systemic inflammatory condition associated with significant cardiometabolic comorbidities, including obesity, type 2 diabetes mellitus (T2DM), and cardiovascular (CV) disease. These comorbidities are interlinked via shared immunopathogenic mechanisms, notably chronic low-grade inflammation driven by Th1/Th17 cytokines such as TNF, IL-6, and IL-17. Obesity, in particular, exacerbates PsD severity and treatment resistance, underscoring the need for integrated therapeutic strategies. This scoping review investigates the biological rationale and evidence for the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in PsD. FINDINGS: Originally developed for T2DM, GLP-1RAs have demonstrated efficacy in reducing weight and improving glycemic control and CV outcomes. Evidence also suggests immunomodulatory properties through modulation of key inflammatory pathways and immune cell activity. We examined studies addressing: (1) the impact of obesity, T2DM, and CV disease on PsD; (2) outcomes of GLP-1RAs in these comorbidities; and (3) their potential in related rheumatologic and dermatologic diseases. GLP-1RAs show promise in reducing PsD burden by improving metabolic parameters and reducing systemic inflammation. Early clinical and preclinical data suggest benefits also in rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, and hidradenitis suppurativa. IMPLICATIONS: GLP-1RAs represent a novel, multifaceted therapeutic option in PsD, targeting both metabolic and inflammatory components. Further clinical trials are warranted to define their role in comprehensive PsD management and validate their disease-modifying potential.
Periodontitis, subclinical myocardial injury, and cardiovascular mortality among US adults: a population-based study.
Guo DC, He WB, Chen ZT … +4 more , Wang JF, Shen T, Zhang HF, Liu DP
Inflamm Res · 2025 Nov · PMID 41266855 · Publisher ↗
BACKGROUND: Periodontitis has been associated with an increased risk of atherosclerotic cardiovascular disease; however, its association with subclinical myocardial injury remains scarce. The purpose of this study was to...
BACKGROUND: Periodontitis has been associated with an increased risk of atherosclerotic cardiovascular disease; however, its association with subclinical myocardial injury remains scarce. The purpose of this study was to investigate the association between periodontitis, cardiac biomarkers of subclinical myocardial injury, and cardiovascular mortality in the general U.S. METHODS: We analyzed data from 9202 participants initially free of cardiovascular disease in the 1999-2004 National Health and Nutrition Examination Survey. The grade of periodontitis was categorized into normal, mild, and moderate-severe. Survey-weighted multiple linear regression model assessed the association between periodontitis and cardiac biomarkers, including high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Survey-weighted multiple Cox regression model was utilized to estimate the association between periodontitis and cardiovascular disease mortality. RESULTS: The mean age of participants was 40.65 ± 0.32 years, with 48.44% being men. The individuals with mild and moderate-severe periodontitis had significantly elevated hs-cTn and NT-proBNP, which indicated impaired cardiac structure and function, compared with non-periodontitis individuals. After controlling confounding covariates, moderate-severe periodontitis was significantly correlated with elevated hs-cTnT and NT-proBNP (β coefficients: 0.055, 95% CI 0.004 to 0.106; β coefficients: 0.188, 95% CI 0.077 to 0.300, respectively). Sensitivity analysis and subgroup analysis further verified the robustness of the results. Over a 17.5-year follow-up period, individuals with moderate-to-severe periodontitis exhibited a 44.9% higher risk of cardiovascular mortality compared to those without periodontitis (hazard ratio: 1.449, 95% CI: 1.027 to 2.044). CONCLUSION: In individuals without established cardiovascular disease, moderate-severe periodontitis was associated with higher concentrations of hs-cTn and NT-proBNP, as well as an increased risk of cardiovascular mortality. These results emphasize the importance of maintaining optimal oral health.
Transcriptomic profiling reveals a dramatic inflammatory shift in osteal macrophages during colitis-induced osteoporosis.
Suzuki R, Chen L, Endo T … +10 more , Tokuhiro T, Nakajo M, Ogawa Y, Alhasan H, Ebata T, Takahashi D, Kadoya K, Takahata M, Iwasaki N, Terkawi MA
Inflamm Res · 2025 Nov · PMID 41266820 · Publisher ↗
OBJECTIVE: Colitis disrupts the intestinal barrier, leading to increased permeability and the translocation of harmful microbial components into the circulation and distant organs, including bone. Given that macrophages...
OBJECTIVE: Colitis disrupts the intestinal barrier, leading to increased permeability and the translocation of harmful microbial components into the circulation and distant organs, including bone. Given that macrophages serve as both frontline immune defenders in tissues and key regulators of bone homeostasis, this study investigates molecular alterations in osteal macrophages (Omacs) and their contribution to bone loss in a murine model of colitis-induced osteoporosis. METHODS: Colitis-induced osteoporosis was established by administering DSS in drinking water for 5 days. Omacs were isolated from bone tissue and subjected to bulk RNA-seq analysis, phagocytosis assays and co-culture models with osteoblasts or osteoclast precursors. RESULTS: RNA-seq data of Omcas demonstrated a shift towards an inflammatory phenotype under colitis conditions, which was accompanied by bone loss in mice. The upregulated genes in these cells were most significantly enriched in IL-17, NF-κB, and TNF signaling pathways. Importantly, these cells exhibited decreased phagocytic activity and were able to disrupt osteoblast differentiation and promote osteoclast differentiation in vitro. CONCLUSIONS: These results indicate that colitis triggers a significant inflammatory response in Omacs, which can contribute to bone metabolic dysfunction. Modulating the activation of inflammatory pathways may offer a potential therapeutic avenue for treating colitis-induced osteoporosis.
Novel insights into the effect of sTIM-3 on NLRP3 inflammasome via interacting with ASC.
Zhang X, Han N, Xu Z … +10 more , Tong Z, Ren X, Sun Y, Li C, Yue X, Wu Z, Liang X, Ma C, Wang P, Gao L
Inflamm Res · 2025 Nov · PMID 41266817 · Publisher ↗
OBJECTIVE: T cell immunoglobulin and mucin-domain containing-3 (TIM-3) plays a critical regulatory role in a variety of diseases. Human soluble TIM-3 (sTIM-3) is known to be generated through proteolytic cleavage of memb...
OBJECTIVE: T cell immunoglobulin and mucin-domain containing-3 (TIM-3) plays a critical regulatory role in a variety of diseases. Human soluble TIM-3 (sTIM-3) is known to be generated through proteolytic cleavage of membrane-bound TIM-3 by the A disintegrin and metalloprotease, however its precise role in inflammation remains largely unclear. This study aims to define the specific function of sTIM-3. METHODS: In this study, the role of sTIM-3 was investigated using in vivo models of experimental autoimmune encephalomyelitis (EAE) and septic shock. Mechanistic insights were gained through biochemical analyses of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome pathway. RESULTS: We found that sTIM-3 alleviated disease severity in both EAE and septic shock. This protective effect was achieved through the inhibition of NLRP3 inflammasome activation. Mechanistically, sTIM-3 interacted with the adaptor protein Apoptosis-associated speck-like protein containing a CARD (ASC), thereby dampening its oligomerization and subsequent assembly of the active NLRP3 inflammasome complex. CONCLUSION: Our findings establish sTIM-3 as a promising therapeutic candidate for mitigating inflammation caused by excessive NLRP3 inflammasome activation, providing novel insights into potential interventions for various inflammatory diseases.
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