Inflammation Research最新文献

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 CD79B⁺B 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.

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.

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.

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.

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 I² 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; I² = 96.0%), ESR (pooled SMD = - 1.49, 95% CI - 3.71 to 0.72; I² = 91.7%), or CRP (pooled SMD = - 1.65, 95% CI - 3.88 to 0.58; I² = 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.

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.

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.

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.

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.

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.