Steroid-resistant asthma (SRA) is a severe refractory condition characterized by resistance to corticosteroids. This study investigated the molecular mechanisms by which ozone (O3) exposure facilitates mitochondrial oxidative stress (mtOS) and inflammatory responses in SRA. Mouse or human bronchial epithelial cells (BEAS-2B) were treated with HDM while exposed to O3 and treated with dexamethasone to simulate SRA in vitro and in vivo, respectively. Lung function testing was performed to assess airway hyperreactivity. Histological staining was conducted to examine lung tissue damage, inflammatory cell infiltration, and airway goblet cell hyperplasia. ELISA and immunohistochemistry were performed to detect inflammatory responses. GRα nuclear transport, GRβ protein expression, mtOS, and Ca2+ levels were measured. The expressions of METTL14 and UCP2 and their regulatory relationship were examined. The effects of the METTL14/m6A/UCP2 axis in SRA mice were validated through METTL14 knockout and UCP2 overexpression rescue experiments. O3 exposure reversed the improvement effect of dexamethasone on airway hyperreactivity, inflammation, and mtOS in asthmatic mice. O3 inhibited UCP2-mediated Ca2⁺ influx, which exacerbates mtOS and inflammatory responses in BEAS-2B cells under SRA conditions. Lower serum METTL14 and UCP2 were associated with poorer lung function in SRA patients. Overexpression of UCP2 or METTL14 partially reversed the promoting effect of O3 on mtOS and inflammation in BEAS-2B cells under SRA conditions. METTL14 upregulated UCP2 expression in an m6A-YTHDF1-dependent manner. Knockout of METTL14 exacerbated mtOS and inflammation in SRA mice. O3 exposure promotes Ca2+ influx by blocking the METTL14/m6A/UCP2 axis, promoting mtOS and inflammatory responses in SRA.
This review focused on current evidence regarding the mechanisms underlying regulatory T cell (Treg) dysfunction in atopic dermatitis (AD), with particular emphasis on Treg instability, tissue microenvironmental reprogramming, inflammatory plasticity, and the skin-gut immune axis, and evaluated Treg-directed therapeutic strategies. Experimental and clinical studies investigating Treg functions, tissue microenvironment, immune regulation, microbial dysbiosis, and therapeutics in AD were critically analysed and integrated into a mechanistic framework. AD is a chronic inflammatory skin disease with epidermal barrier dysfunction, pruritus, microbial dysbiosis, and immune dysregulation. Current evidence suggests that Treg abundance, phenotype, localization, and suppressive function may differ across AD endotypes and tissue compartments. Functional impairment or maladaptive plasticity might play a role in persistent inflammation within specific Treg populations. This may link to FOXP3 instability, altered IL-2/STAT5 signaling, metabolic strain, cytokine-induced destabilization, plasticity, keratinocyte-derived alarmins, inflammatory dendritic cells, Staphylococcus aureus colonization, and the skin-gut microbial axis. Novel therapeutics may restore immune tolerance beyond conventional anti-inflammatory treatment, including Treg-selective IL-2 agonists, microbiome-based therapy, and antigen-specific regulatory approaches. Treg dysregulation may represent a major component in AD pathogenesis, but its causality for disease persistence and therapeutic reversibility is yet to be elucidated.
Rationale Atherosclerosis (AS) is a chronic inflammatory disease of the arterial walls, initiated by endothelial dysfunction and subendothelial lipid deposition. Even though treatments to lower lipids have improved, there are still not many options that specifically tackle inflammation-caused endothelial dysfunction in the early stage of AS. Spironolactone (SP) has been shown to be beneficial in reducing cardiovascular complications, and while it acts as a pharmacological inhibitor of pannexin 1 (Panx 1), the mechanism by which SP modulates Panx 1 in endothelial cells (ECs) during inflammation remains unclear.Objective To identify Panx 1 on ECs is a key mediator through which SP ameliorates vascular inflammation, lowers oleic acid (OA)-induced intracellular neutral lipid accumulation, and sustains the function of ECs, thereby attenuating early AS.Methods and results In vivo, SP administration significantly ameliorated plasma biochemical parameters, mitigate aortic inflammation and reduced lipid deposition, thereby reducing endothelial activation and alleviating endothelium damage in an early AS model established by feeding ApoE-/- mice a high-fat diet. Non-targeted metabolomic profiling revealed that SP profoundly remodeled the plasma metabolome, indicating systemic metabolic restoration. In vitro, SP reversed TNF-alpha induced activation of ECs and attenuated OA-induced neutral lipid accumulation in human umbilical vein ECs. However, no significant difference of Panx 1 expression in ECs was observed between normal and abnormal endothelial function in AS mouse models or clinical subjects. Mechanistically, SP targeted Panx 1 as a pivotal mediator of the inflammatory response, not only inhibiting TNF-alpha induced Panx 1 expression but also significantly blocking the functional opening of Panx 1 channels, thereby preventing subsequent Ca2+ influx. This attenuation of intracellular Ca2+ overload was essential for the protective effects of SP against both endothelial dysfunction and inflammation-mediated OA to induce intracellular neutral lipid accumulation. Furthermore, we demonstrated that SP suppresses NF kappa B signaling activation by inhibiting the Panx 1-dependent intracellular Ca2+ rise, revealing a mechanistic Panx 1/Ca2+/NF kappa B axis that regulates inflammation-driven intracellular neutral lipid accumulation.Conclusion Taken together, these findings indicate that SP mitigates early AS by reduced endothelial activation and attenuating inflammation-driven intracellular neutral lipid accumulation via suppression of the Panx 1/Ca2+/NF kappa B signaling axis. This study establishes Panx 1 as a promising therapeutic target for early vascular intervention in AS and considers SP as a potential candidate for prevention of atherosclerotic cardiovascular disease.
Psoriasis is a chronic inflammatory skin disease characterized by aberrant production of IL-17 or autoactivation of IL-17 downstream signaling. Anti-IL-17 antibodies are highly effective for most psoriasis patients, but their efficacy is limited when the disease is driven by downstream signaling events, such as ACT1 mutation or N4BP1 deficiency. MLN4924 is a small‑molecule neddylation inhibitor with promising clinical potential. However, its therapeutic value in psoriasis remains unknown, particularly in the context of N4BP1 loss and ACT1 autoactivation. Inflammatory cellular and mouse models, including IL-17 stimulation, N4BP1 knockout, and Act1 overexpression, were used to evaluate the effect of MLN4924 on the expression of IL-17 downstream target genes. The mechanism of action of MLN4924 was explored by assessing MAPK phosphorylation levels and Act1 subcellular localization. N4BP1 deficiency, IL-17 stimulation, or Act1 overexpression all strongly induced activation of IL-17 pathways or overproduction of downstream pro‑inflammatory factors such as CXCL1, CCL20, CCL2, CXCL8, CXCL10, and TNFα. Strikingly, in all models tested, MLN4924 treatment fully blocked the overproduction of these pro‑inflammatory factors. Mechanistic studies revealed that the action of MLN4924 was independent of MAPK inhibition or the neddylation pathway, but instead relied on inhibition of Act1 nuclear localization. In vivo experiments demonstrated that topical application of MLN4924 markedly ameliorated erythema, scaling, and epidermal thickening in the dorsal skin of mice, with particularly pronounced efficacy in N4BP1‑knockout animals. MLN4924 fully blocks the overproduction of IL-17-downstream targets driven by ACT1 hyperactivation or N4BP1 deficiency and efficiently alleviates psoriasiform dermatitis progression through inhibition of Act1 nuclear localization.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disorder in which type 2 (T2) inflammation represents the predominant endotype, characterized by eosinophilic infiltration and activation of IL-4, IL-5, and IL-13 pathways. Patients with T2-CRSwNP frequently present with asthma, NSAID-exacerbated respiratory disease, and a high risk of recurrence. Conventional management based on intranasal or systemic corticosteroids and endoscopic sinus surgery may relieve symptoms but often fails to achieve sustained disease control in patients with persistent T2 inflammation. This review summarizes the immunopathology and risk stratification of T2-CRSwNP and discusses current evidence and practical considerations for biologic therapy within a structured clinical decision framework. Biologic therapies targeting IL-4Rα, IL-5/IL-5R, IgE, and TSLP have demonstrated efficacy in reducing polyp burden, improving symptoms, and decreasing systemic corticosteroid exposure. However, in the absence of robust head-to-head comparisons, optimal patient selection and defining sustainable long-term maintenance strategies remain clinical challenges. Integrating inflammatory profiles, disease burden, and structured follow-up may support individualized treatment and sustained disease control.
