Sustained low-grade inflammation is increasingly recognized as a central element in how polycystic ovary syndrome (PCOS) develops. Here we set out to clarify what role follicular fluid (FF)-borne exosomal miR-424-5p plays in shaping ovarian inflammation and how this ties in with the ovulatory problems seen in PCOS. Across FF samples taken from patients, miR-424-5p levels tracked inversely with pro-inflammatory cytokine concentrations to a striking degree. When granulosa cells (GCs) were challenged with lipopolysaccharide (LPS), delivering exosomal miR-424-5p dampened cytokine release and restored the expression of ovulation-linked genes. Using a dual-luciferase reporter assay, we traced this effect to FGF2, which miR-424-5p binds directly, and we found FGF2/FGFR1 signaling to be conspicuously raised in PCOS. In dehydroepiandrosterone (DHEA)-treated rats modeling the syndrome, giving exosomal miR-424-5p eased ovarian inflammation and brought back part of the lost ovulatory capacity. Taken together, the data suggest that exosomal miR-424-5p tempers ovarian inflammation in PCOS by holding the FGF2/FGFR1 axis in check, which casts fresh light on the follicular abnormalities that mark this condition.
Diabetic nephropathy (DN), a major diabetic microvascular complication, is the primary cause of end-stage renal disease worldwide. It is characterized by mesangial cell fibrosis and chronic inflammation, which current treatments cannot completely reverse. Baicalein, a major flavonoid from Scutellaria baicalensis Georgi, has anti-inflammatory and antifibrotic activities, but its role and mechanism in high glucose (HG)-induced mesangial cell injury (a key DN feature) remain unclear. This study investigated baicalein's effects on rat glomerular mesangial cells (HBZY-1) and validated key findings in human primary glomerular mesangial cells. CCK-8 assay identified 10-20 μM as baicalein's non-cytotoxic range (cell viability ≥ 90%). Further experiments demonstrated that baicalein dose-dependently inhibited HG-induced increases in fibrotic markers (α-SMA, FN, COL1A1) at both mRNA (qRT-PCR) and protein levels (Western blot, immunofluorescence), and reduced proinflammatory cytokines (IL-6, TNF-α, MCP-1) at transcriptional (qRT-PCR) and secretory levels (ELISA). Western blot analysis demonstrated that baicalein dose-dependently activated the AMPK pathway by increasing p-AMPK/AMPK at Thr172 and inhibited the TGF-β/Smad pathway by reducing TGF-β1 and p-Smad2/3/Smad2/3. Using the AMPK inhibitor Compound C, we confirmed baicalein's anti-fibrotic, anti-inflammatory, and TGF-β/Smad-inhibitory effects were closely associated with AMPK activity. Molecular docking showed baicalein stably bound the AMPK β-subunit's C-terminal domain (PDB ID: 4EAK), suggesting a potential interaction that may contribute to AMPK activation. Baicalein protects against HG-induced mesangial cell injury via an AMPK-associated mechanism linked to the suppression of fibrosis and inflammation, highlighting it as a promising DN therapeutic candidate for further preclinical and clinical study.
Recessive dystrophic epidermolysis bullosa is an inherited skin disorder characterized by fragile skin, blistering, and chronic wounds. Keratinocytes, the primary cells in the epidermis, are directly affected by persistent injury in recessive dystrophic epidermolysis bullosa, contributing to chronic inflammation. HMGB1 (high mobility group box 1) is elevated in the serum of individuals with recessive dystrophic epidermolysis bullosa. However, its role in keratinocyte inflammation remains unclear. In this study, we report an increase in HMGB1 expression in keratinocytes at chronic wound sites compared with that on matched nonwounded skin from an individual with recessive dystrophic epidermolysis bullosa, suggesting a potential link to the upregulation of local proinflammatory stimuli. Pharmacologic inhibition of HMGB1 using inflachromene reduced lipopolysaccharide-induced secretion of proinflammatory cytokines in keratinocytes, supporting a role for keratinocyte-specific HMGB1 in inflammatory response. Surprisingly, deletion of HMGB1 alone or together with its paralog HMGB2 did not suppress the release of proinflammatory cytokines in response to lipopolysaccharide. Furthermore, inflachromene still reduced the secretion of proinflammatory cytokines in HMGB1- and HMGB2-knockout cells. This unexpected discrepancy between genetic deletion and pharmacologic inhibition points to a more complex role for HMGB1 or off-target effects of the compound. These findings suggest that HMGB1 may contribute to proinflammatory signaling in keratinocytes; however, its exact function needs further investigation.
Exposure to heavy metals has been implicated in insulin resistance (IR), yet the mechanisms remain unclear. Systemic inflammation may link metal exposure to metabolic outcomes. We analyzed 3042 U.S. adults from NHANES 2021-2023. Blood lead, cadmium, mercury, selenium, and manganese were examined in relation to IR (HOMA-IR), with high-sensitivity C-reactive protein (hs-CRP) as the inflammatory mediator. We used survey-weighted regression, Baron-Kenny mediation, and weighted quantile sum (WQS) regression for the mixture, stratified by sex; sensitivity analyses additionally adjusted for body mass index (BMI) and smoking. In primary models, lead, cadmium, and mercury were inversely associated with HOMA-IR (lead β = -0.259), as was a WQS mixture dominated by these metals, and hs-CRP significantly mediated several associations. After additional adjustment for BMI and smoking, the inverse single-metal and mixture associations remained significant but were attenuated by roughly half, indicating substantial adiposity confounding. hs-CRP continued to mediate a smaller but significant share (roughly 10% to 30%, vs. 25% to 43% before adjustment). The positive manganese association did not survive BMI adjustment and is not robust. Mediation was larger in females and younger adults. In a nationally representative sample, blood lead, cadmium, and mercury, individually and as a mixture, were inversely associated with insulin resistance, with hs-CRP mediating a smaller but significant share after adjustment for adiposity. Because the associations are substantially attenuated by BMI and the design is cross-sectional, reverse causation is plausible. These findings are hypothesis-generating and motivate prospective studies.
This commentary provides a critical appraisal of the recent study by Chen and colleagues, which demonstrated that cutaneous palmitic acid (PA) aggravates atopic dermatitis (AD) by driving S-palmitoylation of transient receptor potential vanilloid 1 (TRPV1) in sensory neurons and Mas-related G protein-coupled receptor B2 (MRGPRB2) in mast cells, with the serum/glucocorticoid regulated kinase 1 (SGK1)/neural precursor cell expressed developmentally downregulated protein 4-like (NEDD4L) axis serving as a critical contextual regulator. While the original study offers compelling in vivo genetic validation, several mechanistic and translational questions remain unresolved. Here, we prioritize three areas for future investigation: first, the upstream sources of elevated cutaneous PA-whether derived from keratinocyte lipogenesis, systemic circulation, or microbial production-remain undefined and warrant cell-type-specific genetic interrogation complemented by stable-isotope tracing, spatial lipidomics, and germ-free models. Second, the functional divergence of S-palmitoylation on TRPV1 (promoting degradation) versus MRGPRB2 (conferring stabilization) suggests involvement of distinct palmitoyl acyltransferases (PATs) or context-dependent effects; we propose testable hypotheses including the candidate PAT zDHHC4 for TRPV1 and advocate for cell-based reconstitution, cysteine-mutant rescue, and PAT screening approaches. Third, the anatomical divergence in spinal inflammation between nape and ear models raises questions about the generalizability of central neuroimmune engagement across AD phenotypes, with implications for preclinical model selection and clinical subset stratification. Addressing these questions will clarify whether the PA-palmitoylation-neuroimmune axis represents a tractable therapeutic target and will inform the development of precision interventions that interrupt this pathway without disrupting broader homeostatic palmitoylation, while recognizing that current lack of cell-type-specific palmitoylation inhibitors remains a major hurdle.
Eukaryotic mitochondria are characterized by several features that represent vestiges of their prokaryotic ancestry. One such feature is the N-terminal formylation of proteins encoded by mitochondrial DNA that undergo translation by mitochondrial ribosomes. N-formylated proteins are also released by bacteria and trigger activation of immune cells such as neutrophils. Growing evidence indicates that circulating levels of mitochondrial formyl proteins are elevated in the serum of patients with excessive inflammatory responses. However, the mechanisms by which they are released into circulation are not known. In this study, we have identified vascular endothelial cells as a source of Pink1-dependent release of mitochondrial formyl proteins in response to inflammatory mediators. Mechanistically, the mitophagy mediator Pink1 is stabilized by inflammatory activation of endothelial cells, promoting mitophagy and mitochondrial formyl peptide release both in mice and primary human endothelial cells. Using nanoparticle delivery of Pink1-targeting sgRNA in mice expressing endothelial-specific Cas9, we developed a mouse model in which Pink1 is specifically depleted in the endothelium. Deletion of endothelial Pink1 decreased circulating formyl peptide levels, lowered lung neutrophil infiltration and reduced mortality in mice. We thus propose that endothelial cells upregulate pro-inflammatory mitophagy in response to inflammation, leading to the release of mitochondrial formyl peptides and detrimental neutrophil recruitment into the lung.
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BackgroundThe neutrophil percentage-to-albumin ratio has shown prognostic significance across several chronic diseases; however, its relevance within the context of sleep disorders has not been investigated.MethodsThis study utilized data from the National Health and Nutrition Examination Survey for the years 2005-2014 to explore the connection between the neutrophil percentage-to-albumin ratio and all-cause mortality in people with sleep disorders. Mortality risk was assessed using Cox regression, and the analyses included restricted cubic spline, Kaplan-Meier survival, subgroup, and time-dependent receiver operating characteristic curve analyses.ResultsA positive correlation was identified between the neutrophil percentage-to-albumin ratio and mortality risk among individuals with sleep disorders (hazard ratio = 1.09, 95% confidence interval: 1.05, 1.14). A comparison between the highest (Q4) and lowest (Q1) quartiles revealed that patients in Q4 had an 86% higher mortality risk (hazard ratio = 1.86, 95% confidence interval: 1.31, 2.65). Subgroup analysis further confirmed consistency across different demographic and clinical strata (all p for interaction > 0.05). Furthermore, the neutrophil percentage-to-albumin ratio demonstrated strong predictive performance for early mortality risk in patients with sleep disorders (1-year area under the curve = 0.751, 95% confidence interval: 0.693, 0.808).ConclusionsAmong patients diagnosed with sleep disorders, higher levels of NPAR are independently linked to an elevated risk of all-cause mortality.
We examined the effects of fucoidan, a sulfated polysaccharide, administered concurrently with the onset of a high-fat diet (HFD) for a short period in C57BL/6 N mice to evaluate its immunological effects under obesity-inducing conditions. Numerous genes that were downregulated in the HFD group relative to the control-diet group were restored in the HFD + fucoidan group; these genes were mainly associated with inflammatory responses and cellular functions, including migration and viability, as identified by DNA microarray analysis. Upstream regulator analysis in ingenuity pathway analysis identified numerous cytokines and inflammatory mediators. Quantitative PCR confirmed that the expression of selected inflammatory cytokine genes-particularly Ifn-γ and Il-5-was decreased in the HFD group but restored in the HFD + fucoidan group. Our study suggests that fucoidan administered concurrently with an HFD attenuates HFD-induced downregulation of inflammatory and immune-related functions, including T-cell and B-cell functions, and may improve HFD-induced immune dysfunction and imbalance.
Congenital absence of mandibular second premolars occur in 2.91-3.22% of individuals, with nearly half of cases being bilateral. Interceptive hemisection of primary second molars promotes mesial drift but exposes the pulp for an extended period. This study investigates histopathological responses of pulp and associated mineralized tissues. Children aged 7-12 in Skaraborg region, Sweden, were screened for over-retained primary mandibular second molars as part of a single-center, blinded, prospective split-mouth randomized controlled clinical trial comparing hemisection with extraction. Mesial roots of 21 hemisected teeth were collected for histopathological analysis of inflammatory infiltrate, pulpal necrosis, fibrosis, and hard tissue formation. Mean interval between distal and mesial root extraction was 11.54 ± 4.3 months. Histopathological analysis revealed no pulpal inflammation in 14% of specimens, acute/subacute inflammation in 38%, chronic inflammation in 48%, and necrosis in 24%. Reparative tertiary dentin with capping occurred in 48% and without capping in 33%. Necrotic mineralized tissue appeared in one specimen. Three patients reported symptoms during follow-up. Prolonged pulp exposure following hemisection induced tertiary dentinogenesis, maintaining pulp vitality for up to 17 months. Despite histological evidence of inflammation or necrosis, most cases remained asymptomatic, indicating remarkable regenerative capacity of primary pulp-dentin complex.
Obstructive sleep apnea (OSA) is frequently complicated by hypertension, with approximately 60% of patients exhibiting both conditions. However, the epigenetic mechanisms underlying this comorbidity remain largely unexplored. N6-methyladenosine (m6A), the most abundant internal RNA modification, has emerged as a critical regulator of cardiovascular pathology, yet its role in OSA-associated hypertension (OSA-HTN) is unknown. Here, we investigated the contribution of m6A RNA methylation to OSA-HTN pathogenesis. In a chronic intermittent hypoxia (CIH) mouse model and hypoxia-stimulated aortic vascular smooth muscle cells (AVSMCs), we observed marked inflammatory injury, pyroptosis, and decreased expression of methyltransferase-like 3 (METTL3) along with global m6A levels. Overexpression of METTL3 significantly attenuated hypoxia-induced pyroptosis and inflammation by downregulating SRY-box transcription factor 4 (SOX4), a pro-inflammatory transcription factor. Mechanistically, CIH suppressed YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2), an m6A reader that directly binds SOX4 mRNA, while METTL3-mediated m6A modification enhanced YTHDF2-dependent SOX4 mRNA degradation. Knockdown of YTHDF2 abolished the suppressive effect of METTL3 on SOX4 stability, confirming a METTL3-m6A-YTHDF2 regulatory axis. This METTL3-dependent regulation of YTHDF2-SOX4 interaction and SOX4 mRNA decay was also validated in mouse aortic endothelial cells. Furthermore, in vivo silencing of SOX4 alleviated CIH-induced pyroptosis and inflammation in cardiac and aortic tissues. Notably, pharmacological activation of METTL3 or METTL3 overexpression similarly attenuated CIH-induced cardiac and aortic tissue injury in OSA-HTN mice. In conclusion, our findings identify a novel METTL3-YTHDF2-SOX4 axis that governs hypoxia-induced pyroptosis and inflammation, providing new mechanistic insights into the epigenetic regulation of OSA-HTN and highlighting potential therapeutic targets.
Viruses are increasingly recognized as potential modulators of oral biofilm ecology and periodontal inflammation, expanding the traditional bacterial paradigm of periodontitis. Members of the Herpesviridae family, including Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), and herpes simplex virus (HSV), are frequently detected in periodontal tissues and may influence disease activity through latency, reactivation, immune modulation, epithelial barrier disruption, and interactions with bacteria. These processes may contribute to local dysbiosis and sustained periodontal inflammation. The potential systemic relevance of oral viruses is biologically plausible but remains incompletely established. Viral persistence or reactivation in oral niches may contribute to systemic immune activation through hematogenous spread, saliva-mediated dissemination, aspiration, or amplification of inflammatory mediators as IL-1β, IL-6, and TNF-α. Accordingly, viruses may act as disease modifiers within the broader relationship between periodontitis and systemic conditions including cardiovascular, metabolic, respiratory, neurogenerative, pregnancy-related, and cancer-associated outcomes. However, the strength of evidence differs across these conditions. Current data support a model in which oral viruses, bacteriophages, bacteria, and fungi form an interconnected biofilm ecosystem that may influence periodontitis progression and systemic inflammatory burden. Nevertheless, most available evidence is observational, associative, or derived from mechanistic experimental models, and definitive proof that viruses are independent etiopathogenic drivers of periodontitis is lacking. Future longitudinal and interventional studies are needed to determine whether viral detection reflects bystander association, disease amplification, or a true pathogenic role, and whether antiviral or phage-based strategies offer clinical benefit beyond established periodontal therapy.
Macrophage foam cell formation is the mark of atherosclerosis (AS). Krüppel-like factor (KLF)11 prevented the development of AS in diabetic conditions. However, it is not clear whether KLF11 inhibits macrophage foam cell formation. High-fat diet (HFD) was administered to ApoE-/- mice to build an in vivo AS model. An adeno-associated virus (AAV) vector incorporating the macrophage-specific promoter CD68 was utilized to construct the macrophage-specific KLF11 overexpression mouse model. Treatment of RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) elicited foam cell formation. Dual luciferase reporter gene assays, ChIP, and RIP were applied to detect interactions between molecules. Pathological changes in arterial tissue were detected by HE staining, and the area of collagenous fibers was measured by Masson staining. Cholesterol efflux and cholesterol uptake were analyzed using NBD-cholesterol and Dil-ox-LDL methods, respectively. Lipid and inflammation levels were assessed using commercially available kits. Adipogenesis was assayed via Oil red O staining. KLF11 expression was downregulated, and overexpression of KLF11 suppressed inflammation, cholesterol levels, and lipid accumulation in AS. Meanwhile, overexpression of KLF11 inhibited ox-LDL-induced foam cell formation. Mechanistically, IGF2BP3 promoted KLF11 stabilization and expression in an m6A-dependent manner, and KLF11 transcriptionally inhibited ATP5B, which prevented NLRP3 inflammasome activation. IGF2BP3 mediated KLF11 stabilization to inhibit macrophage foam cell formation and alleviate AS through transcriptional inhibition of ATP5B to block NLRP3 inflammasome activation.
Negative symptoms are a core component of schizophrenia, affecting up to 60% of individuals with the disorder. They are categorised into primary negative symptoms (PNS), which are intrinsic to the illness, and secondary negative symptoms, which arise from external factors such as depression or medication side effects. They can also be divided into diminished expression and amotivation/anhedonia subtypes. While inflammation has been implicated in schizophrenia and linked to negative symptoms, little is known about whether inflammatory profiles differ between negative symptom subtypes in individuals at Ultra-High Risk (UHR) for psychosis. We conducted a secondary analysis of 147 UHR participants from the Staged Treatment in Early Psychosis (STEP) study to examine whether inflammatory markers (Alpha-2-Macroglobulin, IL-6, CRP, sICAM-1, sVCAM-1, and suPAR) differed across negative symptom subgroups, using multinomial and binomial logistic regression models adjusted for age, sex, smoking, and BMI. Overall, most inflammatory markers were not significantly associated with negative symptom subgroups. However, higher sICAM-1 levels were asscoiated with lower odds of primary negative symptoms compared with no negative symptoms. Additionally, younger age was associated with increased odds of PNS and amotivation, while smoking was associated with higher odds of secondary negative symptoms compared with no negative symptoms. These findings suggest that inflammation may not broadly distinguish negative symptom subtypes at the UHR stage, although sICAM-1 may play a role in early illness processes. Limitations include sample ascertainment, potential misclassification of negative symptoms, and the relatively small number of participants with PNS. Future studies with larger samples and longitudinal designs are needed to clarify whether inflammatory changes contribute to the emergence of specific negative symptom subtypes.
Polyendocrine metabolic ovarian syndrome (PMOS), formerly termed polycystic ovary syndrome (PCOS), is a reproductive disorder with heterogeneous symptoms and severity. Despite extensive research documenting chronic immune dysfunction as a hallmark of PMOS, the specific mechanisms of immune activation remain poorly understood. Emerging evidence suggests that gut-derived bacterial endotoxins, particularly lipopolysaccharide (LPS), can breach intestinal barriers and trigger systemic inflammation via Toll-like receptor 4 (TLR4). This study examined the role of TLR4 in PMOS-like pathology using a letrozole (LET)-induced mouse model. In LET-treated wild-type female mice, serum LPS and its carrier protein LBP were elevated compared to LET-treated TLR4-/- mice. Additionally, TLR4 deficiency attenuated multiple PMOS-like features, including elevated luteinizing hormone, anovulation, and metabolic dysfunction. LET-treated TLR4-/- mice also preserved estrous cycling and fertility, maintained gut barrier integrity, and reduced inflammatory markers. These findings support TLR4 as an important contributor to multiple features of PMOS-like pathology. This novel work highlights TLR4-mediated inflammation as a potential target for anti-inflammatory treatments in women with PMOS.
Atherosclerosis (AS) is a chronic vascular disease characterized by inflammatory response and lipid deposition in the arterial walls caused by endothelial injury. Sinomenine (SIN) could delay AS progression by attenuating endothelial inflammation. However, its role and mechanism in the oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVEC) injury remain unclear. An in vitro model of AS in HUVECs was established using ox-LDL. CCK-8 detected cell viability. ROS, SOD, MDA, TNF-α, IL-β, and IL-6 were evaluated using commercial kits. Western blot was used to detect NLRP3, apoptosis-associated speck-like protein containing ASC, activated caspase-1, GSDMD-N, Arg1, CD206, iNOS, CXCL14, and MEF2A protein levels. CXCL14 mRNA level was measured using RT-qPCR. Binding between MEF2A and CXCL14 promoter was validated using dual-luciferase reporter and ChIP. SIN exposure alleviated ox-LDL-caused oxidative stress, inflammation, pyroptosis, and M1 macrophage polarization in HUVECs. CXCL14 or MEF2A silencing abolished the protective effect of SIN on ox-LDL-caused HUVEC injury. Mechanistically, MEF2A directly interacts with CXCL14 promoter and promotes its transcription. SIN treatment restrained ox-LDL-evoked HUVEC injury and M1 macrophage polarization partly via targeting the MEF2A/CXCL14 axis, providing new insights for future research on the application of SIN in AS treatment.
Liver fibrosis is usually accompanied by abnormal activation of hepatic stellate cells. Exosomal microRNAs play important roles in the development of liver fibrosis. Our previous study confirmed that Ellagic acid (EA) is one of the main bloodstream components of Scutellaria barbata, a traditional Chinese medicinal herb. This study aimed to explore the effects of EA on hepatic stellate cells in liver fibrosis. First, a CCl4-induced mouse model of liver fibrosis was used to evaluate the effects of EA administration on the histopathology and histochemical staining of liver tissue in mice with liver fibrosis, while simultaneously assessing serum markers of liver function; Second, RT-PCR was used to detect fibrosis-related genes, inflammation-related genes and matrix metalloproteinase-related genes. Third, exosome-enriched fraction miRNAs from liver tissues were sequenced and PCR-verified for differential expression. Finally, in vitro experiments were performed on murine hepatic stellate cells (JS-1) and human hepatic stellate cells (LX-2) using flow cytometry and Western blotting (WB) to apoptosis-related proteins. Animal studies demonstrated that Scutellaria barbata and its natural active component EA can significantly ameliorate hepatic histopathology in the mouse model of liver fibrosis. Furthermore, EA effectively improves serum liver function parameters, reduces the expression of fibrosis-related, inflammation-related and matrix metalloproteinase-related genes, and markedly reduces elevated miR-182-5p expression in the fibrotic model. Cellular experiments demonstrated that inhibition of miR-182-5p promotes the expression of proteins associated with apoptosis in hepatic stellate cells, thereby accelerating apoptosis in these cells. In summary, EA from S. barbata may accelerates hepatic stellate cell apoptosis during liver fibrosis by inhibiting miR-182-5p.
The cGAS/STING pathway enables cells to sense cytosolic DNA and mount rapid innate immune responses to infection, cellular stress, and tissue damage. While essential for host defense and immune surveillance, inappropriate or sustained activation of this pathway can drive chronic inflammation, autoimmunity, and disease-associated immune dysfunction, which can promote cancer growth. Effective immunity therefore depends on precise regulatory control that restrains cGAS/STING activity under homeostatic conditions while preserving the capacity for swift and robust responses to diverse danger signals. In this Review, we synthesize emerging principles that regulate cGAS/STING signaling across cellular contexts to control signal initiation, amplification, and termination. We discuss how disruption, persistence, or pathological rewiring of these regulatory processes contributes to immune imbalance across health and disease, promoting chronic inflammation, immunosuppression, and tissue pathology, with particular relevance to tumor progression and therapeutic resistance. Finally, we consider how restoring appropriate cGAS/STING regulation, rather than simply enhancing or inhibiting pathway activity, may reestablish immune homeostasis and improve therapeutic outcomes in cancer and other inflammatory diseases, framing the pathway as a dynamic regulatory circuit rather than a simple linear signaling cascade.
Vagus nerve stimulation (VNS) is a neuromodulatory intervention with antiinflammatory and autonomic regulatory properties. Although its clinical applications have primarily been explored in neurological disorders, its potential role in pulmonary and respiratory outcomes across preclinical and clinical settings remains incompletely characterized and dispersed across different study domains. This scoping review aimed to map the available evidence on the effects of VNS on the pulmonary and respiratory systems, with particular emphasis on inflammatory and autonomic mechanisms. This scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Three reviewers systematically searched PubMed, Web of Science, and the Cochrane Library for studies published between January 2020 and February 2026. Original preclinical and clinical studies investigating invasive or noninvasive VNS and reporting pulmonary, respiratory physiology, autonomic, or inflammatory outcomes were included. A total of 159 records were identified, of which 12 studies met the inclusion criteria. The evidence base was predominantly preclinical. In animal studies, invasive cervical VNS was frequently associated with reductions in pulmonary inflammation, histopathological lung injury, and proinflammatory cytokine expression. Clinical studies were limited and heterogeneous, but generally indicated variable modulation of autonomic function, including changes in parasympathetic activity, as well as heterogeneous effects on systemic inflammatory markers and limited respiratory outcomes. Current evidence suggests that VNS may modulate pulmonary inflammatory responses in preclinical models. However, clinical evidence remains limited and heterogeneous, particularly regarding autonomic and respiratory outcomes. Well-designed clinical trials using standardized stimulation protocols and predefined respiratory end points are needed to clarify its therapeutic potential in respiratory disorders.
The development of rheumatoid arthritis (RA) is a multistage process that often begins decades before the first joint symptoms appear. The first critical turning point is the loss of immunological tolerance [1]. Under the influence of chronic stimuli on the mucous membranes increased citrullination of proteins can occur [1]. Particularly in carriers of the shared epitope, the immune system recognizes these altered proteins as "foreign" and thereby produces anticitrullinated protein antibodies (ACPA), marking the onset of systemic autoimmunity [1, 2]. This primordial phase thus represents a potential therapeutic window of opportunity for preventive interventions [3]. In particular, smoking in conjunction with the presence of the shared epitope is associated with an up to 21-fold increased risk for ACPA-positive individuals [4, 5]. Other modifiable environmental factors such as smoking, obesity, diet and periodontitis also contribute to an increased risk of RA development, and thus represent the first key initial focus of primary prevention. In secondary prevention, recent interventional studies in high-risk individuals (ACPA/RF-positive with arthralgia) have shown mixed results: While hydroxychloroquine (STOP-RA) [8] remained ineffective, methotrexate (TREAT EARLIER) [9] was able to delay disease progression, particularly in ACPA-positive patients [9, 10]. Abatacept has so far proven to be the most promising approach (APIPPRA and ARIAA), with a significant reduction in the progression rate and lasting effects well beyond the treatment period. [11, 12].. The ARIAA long-term data also demonstrate that just 6 months of abatacept treatment delays the development of RA for up to 5 years, with IgA-ACPA-positive patients benefiting particularly [14]. Modern imaging using magnetic resonance imaging (MRI) and ultrasound enables the detection of subclinical inflammation, with tenosynovitis considered a highly sensitive early marker [15, 17]. The new EULAR/ACR risk stratification criteria enable the precise identification of high-risk individuals for prevention studies [18, 21]. The combination of lifestyle modifications and targeted drug intervention in high-risk patients could already be revolutionizing RA prevention today. Die Entstehung der rheumatoiden Arthritis (RA) ist ein mehrstufiger Prozess, der oft Jahrzehnte vor den ersten Gelenksymptomen beginnt. Der erste entscheidende Wendepunkt ist der Verlust der immunologischen Toleranz [1]. Unter dem Einfluss chronischer Reize an den Schleimhäuten kann es zu einer verstärkten Citrullinierung von Proteinen kommen [1]. Insbesondere bei Trägern des Shared Epitope (SE) erkennt das Immunsystem diese veränderten Proteine als fremd und bildet dadurch Anti-citrullinierte Protein-Antikörper (ACPA), was den Beginn der systemischen Autoimmunität markiert [1, 2]. Diese Primordialphase stellt ein mögliches therapeutisches Zeitfenster für präventive Interventionen dar [3]. Insbesondere Rauchen in Zusammenhang mit SE zeigt ein bis zu 21-fach erhöhtes Risiko für ACPA-positive Individuen auf [4, 5]. Weitere modifizierbare Umweltfaktoren wie Adipositas, Ernährung und Parodontitis tragen ebenfalls zu einem erhöhten Risiko für eine RA bei und stellen somit den initialen Ansatzpunkt der Primärprävention dar. In der Sekundärprävention zeigen aktuelle Interventionsstudien bei Hochrisikopersonen (ACPA/Rheumafaktor-positiv mit Arthralgie) unterschiedliche Erfolge: Während Hydroxychloroquin (STOP-RA) [8] unwirksam blieb, konnte Methotrexat (TREAT EARLIER) [9] bei ACPA-positiven Patienten die Lebensqualität verzögern [9, 10]. Abatacept erwies sich als vielversprechendster Ansatz (APIPPRA und ARIAA) mit signifikanter Reduktion der Progressionsrate und anhaltenden Effekten weit über die Behandlungsperiode hinaus [11, 12]. Die ARIAA-Langzeitdaten demonstrieren zudem, dass eine nur 6‑monatige Abatacept-Behandlung die RA-Entwicklung für bis zu 5 Jahre verzögert, wobei IgA-ACPA-positive Patienten besonders davon profitierten [14]. Moderne Bildgebung mittels Magnetresonanztomographie (MRT) und Ultraschall ermöglicht die Detektion einer subklinischen Entzündung, wobei Tenosynovitis als hochsensitiver Frühmarker gilt [15, 17]. Die neuen EULAR/ACR-Risikostratifizierungskriterien ermöglichen eine präzise Identifikation von Hochrisikopersonen für Präventionsstudien [18, 21]. Die Kombination aus Lifestyle-Modifikation und gezielter medikamentöser Interzeption könnte die RA-Prävention revolutionieren.