The skin microbiota has been reframed as a dynamic and active regulator of cutaneous barrier integrity and immune programming, moving beyond its traditional view as a passive microbial community. Dysbiosis represents a complex functional and ecological imbalance that disrupts barrier integrity and may promote sustained inflammatory immune remodeling. This mechanistic axis, in which disruption of the microbiota contributes to barrier failure and immune dysregulation, underpins chronic inflammatory skin conditions. Conventional antibiotic-centered therapies often fail to restore microbial homeostasis or immune balance, highlighting their limitations. Emerging precision microbiome therapeutics focus on targeted modulation of microbial function, signaling pathways, and ecological restoration to repair barrier defects and recalibrate immune responses. This review synthesizes current evidence linking skin microbiota dysbiosis with barrier dysfunction, inflammatory immune remodeling, and emerging microbiome-directed therapeutic strategies. We propose an integrative framework linking ecological disruption, epithelial barrier injury, and immune dysregulation while highlighting unresolved mechanistic, translational, and knowledge gaps, such as detailed molecular mechanisms of host-microbiota interactions and challenges in translating findings into clinically effective personalized interventions. Future research should prioritize multi-omics integration and biomarker-driven stratification to advance precision dermatology therapeutics grounded in mechanistic insights of skin microbial ecology.
Staphylococcus aureus is an opportunistic pathogen implicated in skin and soft-tissue infections and chronic inflammatory skin diseases, such as atopic dermatitis. These infections can range from mild to potentially life-threatening systemic illnesses progressing to bacteremia, endocarditis, and sepsis. Mast cells, traditionally recognized for their role in allergies, are highly abundant within the skin and are gaining recognition for their contribution to bacterial defense. Here, we discuss the role of mast cells in three models of S. aureus skin infection according to skin depth: epicutaneous sensitization, intradermal injections, and subcutaneous injections. During S. aureus skin infection, mast cells become activated and accumulate in infected skin, recognize bacterial toxins, and modulate the activity of other immune cells, including neutrophils and dendritic cells. We discuss areas of research that should be the target of future studies, such as neuroimmunology, infected excisional wounds, and risk of systemic illness. Our review aims to bring attention to the host-pathogen interaction between mast cells and S. aureus in the skin, both to encourage deeper investigation and inform the development of immunomodulatory-based therapeutics.
Top: At increasing cellular resolution, the Alegbe et al. report that expression quantitative trait loci (eQTLs) are enriched in enhancer regions rather than promoters. They speculate that enhancer eQTLs only come into effect during certain cellular contexts, making them more tolerable. Bottom: Alegbe et al. identify an enrichment of eQTLs affecting Wnt pathway regulators in inflammatory bowel disease (IBD) epithelium, suggesting a reduced capacity for regeneration. Additionally, the authors show an enrichment of interaction eQTLs (ieQTLs) in IBD epithelium that become active only during inflammation.
Muco-obstructive lung diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis, are characterized by excessive mucus production, airway surface dehydration, impaired mucociliary clearance, and progressive lung function decline. As the efficacy of current therapies often declines with muco-obstructive disease progression, contributing significantly to morbidity and mortality, there is a need for improved treatments that address underlying defects in mucus homeostasis and airway physiology. In this study, we evaluate the effects of carbocisteine, a mucoactive therapeutic, in the βENaC-transgenic (βENaC-Tg) model of muco-obstructive lung disease. Short-term carbocisteine administration significantly reduced airway mucus obstruction, potentially through decreased concentrations of Muc5ac and Muc5b. Notably, carbocisteine treatment modulated key inducers of mucus production, such as interleukin (IL)-13 and the upstream promoter cytokine IL-17, suggesting broader effects on mucoregulatory pathways. Carbocisteine administration was observed to alter mononuclear cell populations, impacting specific inflammatory subsets of CD11b alveolar macrophages and Ly6c monocytes, indicating immunomodulatory effects, either directly or secondary to improved mucus clearance. However, despite changes in immune cell populations, short-term administration failed to mitigate lung damage and inflammation associated with established muco-obstructive lung disease. These findings demonstrate the potent mucoactive effect of carbocisteine in established muco-obstructive lung disease, through a broader mechanism of action than previously understood, with the potential to modulate inflammatory responses for preventive or long-term treatment strategies.
Lysosomes are central regulators of cellular homeostasis, integrating catabolic and anabolic reactions to sustain metabolism. In cancer, however, lysosomal function is not merely upregulated but selectively rewired into distinct, context-dependent states that actively drive tumor immune evasion. This review proposes a conceptual framework linking metabolic, oxidative, oncogenic, and inflammatory pressures to six dominant lysosomal rewiring programs. Chronic nutrient deprivation and hypoxia activate AMPK-ULK1 and HIF signaling, promoting TFEB/TFE3-dependent lysosomal biogenesis, hyper-acidification, and autophagosome-lysosome fusion, collectively degrading immune effectors such as IL-1β and MHC complexes and impairing T-cell priming. Disseminated tumor cells exploit TPC2-mediated Ca2+ signaling and GLS1-dependent metabolism to buffer oxidative stress and support metastatic colonization, while dysregulated PI3K-AKT-mTOR and MYC signaling drive lysosomal peripheralization and lysosomal biogenesis through Arl8b-BORC-kinesin complexes, facilitating cathepsin-mediated exocytosis and MHC-I degradation. Chronic inflammation, sustained by tumor-associated macrophages, myeloid-derived suppressor cells, and IL-6/IL-10 gradients, further reinforce immune suppression. Beyond mechanisms, we also assess the translational readiness of the implicated molecular mediators, distinguishing those with established pharmacological outcomes, such as PI3K-AKT-mTOR inhibitors and repurposed chloroquine/hydroxychloroquine, from mediators that remain strictly preclinical, including TPC2, Arl8b-BORC, and CMTM6/DHHC3, or that are currently undruggable, such as TFEB/TFE3. By framing lysosomes as state-specific orchestrators of immune escape rather than uniform stress organelles, this review offers a mechanistic and translational roadmap for developing lysosome-directed strategies to restore anti-tumor immunity.
This study investigates the role of CIT gene in uterine corpus endometrial carcinoma (UCEC) progression, focusing on its regulation by m6A methylation. Bioinformatics and experimental analyses (EdU, colony formation assay, Dot blot, MeRIP-PCR, RNA pull-down, qRT-PCR, Western Blotting, apoptosis assay) revealed that CIT was significantly overexpressed in UCEC. Mechanistically, we found that the m6A writer RBM15-mediated CIT mRNA methylation, which was then recognized by the reader IGF2BP1 to enhance CIT mRNA stability and expression. Consequently, this m6A-mediated upregulation of CIT inhibited the Hippo signaling pathway, ultimately suppressing apoptosis and promoting malignant proliferation in UCEC. These findings elucidated a novel RBM15/IGF2BP1-CIT-Hippo axis, providing new theoretical insights and potential therapeutic targets for UCEC.
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe autoimmune complication lacking effective treatments. This study investigates the molecular mechanisms underlying the therapeutic effects of licorice-ginger decoction (GGD) in experimental models relevant to arthritis-associated lung fibrosis. Utilizing network pharmacology, transcriptomic sequencing, and molecular docking analyses, we identified the STAT1/ICAM1/IL-17A signaling pathway as crucial for GGD efficacy. Experimental validation in both cellular and murine models demonstrated that GGD markedly alleviated body weight loss, reduced arthritis severity, and improved pulmonary pathological injury under inflammatory arthritis conditions. Mechanistic analyses revealed direct binding of Kae and QR to STAT1/ICAM1, leading to IL-17A inhibition and mitigation of epithelial-mesenchymal transition (EMT) and fibroblast activation. Notably, overexpression of STAT1 attenuated the therapeutic effects of GGD. This study provides mechanistic insights into the anti-inflammatory and antifibrotic effects of GGD in experimental models relevant to arthritis-associated lung fibrosis and offers a potential framework for future mechanistic studies and translational research of classical Chinese formulations.
Ubiquitin C-terminal hydrolase L1 (UCHL1) is a highly conserved deubiquitinating enzyme that has transitioned from being viewed as a "brain-specific" protein to a global regulator of cellular proteostasis and signal transduction. As a key component of the ubiquitin-proteasome system (UPS), UCHL1 maintains the intracellular free ubiquitin pool through its C-terminal hydrolase activity, while also exhibiting atypical ligase-like functions and acting as a molecular scaffold for signaling complexes. Beyond its classical role in neurons, increasing evidence suggests that UCHL1 participates in diverse pathological conditions including neurodegeneration, cancer, cardiovascular and metabolic diseases, as well as musculoskeletal disorders. Through regulation of protein turnover, oxidative stress, inflammatory signaling, and cell survival, UCHL1 emerges as a context-dependent regulator with dual protective and pathogenic roles. This review explores the sophisticated multi-level regulation of UCHL1, ranging from transcriptional control to epigenetic silencing and posttranslational modifications, summarizes the recent research progress of UCHL1 in various systems, and elaborates on its mechanism of action in various conditions, including neurological and musculoskeletal disorders.
Neutrophils are a key component of the immune system, integrating antimicrobial and immunomodulatory functions through various strategies, including phagocytosis, degranulation, generation of reactive oxygen species (ROS), and release of neutrophil extracellular traps (NETs). Owing to their complexity and involvement in a wide range of conditions, including autoimmune diseases, neutrophils have emerged as a major focus of biomedical research. However, it should be noted that neutrophil studies face significant challenges, including short lifespan, terminal differentiation, tendency to spontaneous activation, and donor variability. Moreover, resistance to genetic modifications limits the detailed investigation of gene function and signaling pathways in neutrophil biology. To overcome these constraints, a range of experimental models has been developed. In this review, we present a guide to the currently available neutrophil models (HSPC, iPSC, HL-60, PLB-985, NB4, Kasumi-1, ER-Hoxb8), highlighting their strengths and limitations, with particular emphasis on their value as genetically modifiable platforms. Additionally, we provide an insight into the mechanisms governing neutrophil effector functions.
BLIMP-1, a transcriptional repressor initially identified in plasma B-cell differentiation, also regulates CD8+ T cells and is differentially expressed between naïve and effector/memory CD4+ T cells. However, the functions of BLIMP-1 in human CD4+ regulatory T cells (Tregs) remain unclear. We found BLIMP-1 mRNA levels were low in naïve Tregs from thymus and cord blood, but high in effector/memory Tregs from adult peripheral blood. We confirmed the expression of BLIMP-1 mRNA by microarray of healthy T-cell populations and single-cell RNA-sequencing of SARS-CoV-2 spike-specific CD4+ T cells from convalescent COVID-19 patients. We found activated memory Tregs expressed the highest levels of BLIMP-1, FOXP3, and CD39 transcripts and protein. We show that CD39+ Tregs, regardless of in vitro or in vivo activation, had the highest levels of BLIMP-1 protein expression and significantly more IL-10 mRNA than CD39neg cells. The same result was found through reanalysis of public single cell RNA-sequencing data from lung (tissue and lymph node) SARS-CoV-2 spike-specific Tregs, where cells with high levels of BLIMP-1 mRNA had significantly more IL-10 mRNA than cells with low BLIMP-1 mRNA. Single-cell RNA-sequencing identified an extended transcriptomic profile of these CD39+ Tregs that includes the genes encoding HPGD, CTLA-4, HELIOS, TIGIT, CXCR6, CCR8, and GARP. Together, these data indicate that both circulating and lung resident effector memory Tregs maintain a conserved phenotype following stimulation by cognate antigen. Our data provide further insight into the functions and potential therapeutic targets of the large regulatory T-cell component of CD4+ T-cell responses to pathogens.
A recent study by Gong et al. maps peripheral immune aging using multi-omic profiling and longitudinal influenza vaccination across adults aged 25-90+, revealing midlife (55-65) immune remodeling. Analyses of PBMCs, proteomics, and cell function show early dysregulation before aging, highlighting links to later disease susceptibility before inflammaging.
High-grade central nervous system cancers incur a significant burden of care on society. The combination of therapeutic resistance and high mortality makes it both a challenging target and a devastating diagnosis. Of these, one in two is characterized as glioblastoma (GBM) with a median survival rate of only 13.5 months with the current standard of therapy. Modern interventions, such as PD-1 and CTLA-4 checkpoint inhibition and autologous CAR T cell delivery, remain stymied by both the difficult nature of drug delivery to the brain and the inherent immunosuppressive tumor microenvironment. However, recent advances in the characterization of GBM have unveiled promising new therapeutic avenues aiming to target and eliminate the tumor. In this review, we summarize the mechanisms through which GBM is initiated, localized, and eludes therapy responses and provide an update on recent advances made within this therapeutic space to overcome GBM-mediated immunosuppression. We also discuss the challenges with current and next generational treatment strategies before finally exploring the landscape of potential future therapeutic targets.
The Chinese Immune Multi-Omics Atlas (CIMA) establishes a population-scale immune multi-omics atlas by profiling over 10 million peripheral blood mononuclear cells from 428 Chinese adults using paired scRNA-seq and scATAC-seq. This resource mitigates longstanding European ancestry bias in single-cell genomics and enables cell type resolved regulatory mapping across immune populations. Building on this atlas, CIMA-CLM integrates chromatin sequence features with single-cell transcriptomic context to predict chromatin accessibility and assess noncoding variant effects, exemplified in FOXP3+ regulatory T cells.
During the COVID-19 pandemic, misinformation and vaccine hesitancy disproportionately affected ethnic minority communities across the United Kingdom, including in Wales. Muslim Doctors Cymru (MDC), a grassroots coalition of Muslim healthcare professionals, played a pivotal role in countering this challenge. This paper describes the strategies and impact of MDC's work in addressing health misinformation, building trust, and promoting vaccine uptake among ethnic minority communities in Wales. Through culturally sensitive engagement, multilingual public health messaging, and close collaboration with mosques, community leaders, and local media, MDC delivered targeted outreach that bridged gaps between public health authorities and underserved populations. This case study draws on a grassroots-efforts approach to tackling vaccine inequity using community-based approaches. Findings highlight the importance of culturally competent healthcare communication and the value of community-led initiatives in improving public health outcomes during crises. MDC's model offers a replicable framework for addressing health inequalities and misinformation in diverse populations.
Background. Pediatric liver transplant (LT) recipients are at increased risk of developing a food allergy (liver transplantation-associated food allergy [LTFA]). The underlying immune mechanisms are unknown. Methods. We evaluated the circulating T- and B-cell subsets and serum cytokine profiles of LT recipients with and without LTFA in a cross-sectional cohort study of 43 LT recipients, 8 of whom had LTFA. The T- and B-lymphocyte subsets were analyzed by flow cytometry, and the serum concentrations of 15 cytokines were measured. For comparison, nontransplanted food allergic controls and healthy controls were recruited. Results. Children with LTFA had increased proportions of newly activated (CD69 + ) T cells in both CD4 + and CD8 + subsets ( P = 0.001 and P < 0.001, respectively), as well as CD4 + T cells of the effector memory CD45RA+ phenotype ( P = 0.001), compared with the LT recipients without LTFA. They also had higher serum levels of T helper 2 cytokine interleukin-4 ( P = 0.004) and pro-inflammatory cytokines tumor necrosis factor-alpha and tumor necrosis factor-beta ( P = 0.007 and P = 0.03, respectively). The corresponding broad immune activation was not noted in the food allergic control group. Notably, the entire cohort of LT recipients exhibited significantly larger proportions of activated, memory, effector, and effector memory CD45RA+ subsets of both CD4 + and CD8 + T cells and higher levels of all the measured cytokines compared with age- and sex-matched healthy control. Conclusions. An overall immune activation is prevalent in pediatric LT recipients, and especially profound in those with LTFA. Since the food allergic state per se may only partly account for this immune profile, the ongoing immune activation might be associated with the susceptibility to develop LTFA.
In this 2025 Highlight, we summarize recent advances in T-cell regulation of germinal center (GC) responses. These studies reveal new mechanisms governing follicular helper T (TFH)-cell function and their control of GC dynamics and B-cell fate decisions, providing insights for rational vaccine design and the prevention of GC dysregulation.
Interleukin (IL)-33, a cytokine belonging to the IL-1 family, is produced in various tissues, including the nervous system. As a nuclear-stored alarmin protein, IL-33 is released under cell stress or damage, triggering immune responses through its receptor complex, composed of ST2L and the IL-1 receptor accessory protein (IL-1RAcP). The receptors for IL-33 are expressed in various cell types within the nervous system, including neurons, astrocytes, and microglia, and play a crucial role in neurodevelopment and the pathogenesis of neurological diseases. In neurodevelopment, IL-33 promotes microglial metabolic adaptation and phagocytosis via the IL-33/ST2/Akt axis, modulates glial function to affect neural circuit maturation, and influences oligodendrocyte differentiation. In neurological disorders, IL-33 exerts context-dependent regulatory effects in the nervous system through modulation of myeloid and T-cell responses, maintenance of barrier integrity, promotion of tissue repair, and regulation of neuroimmune homeostasis. In acute CNS injuries such as ischemic stroke and traumatic brain injury, IL-33 is generally associated with anti-inflammatory polarization and enhanced repair, although circulating levels may also reflect injury severity. In chronic neurodegenerative diseases including Alzheimer's and Parkinson's disease, IL-33 is implicated in amyloid-β clearance, remyelination, glymphatic function, and neuroprotection, while dysregulation of the IL-33/sST2 axis correlates with disease progression. In contrast, IL-33 may facilitate tumor progression in glioma. Emerging evidence also supports IL-33 and sST2 as potential biomarkers for diagnosis and prognosis in CNS disorders.
This Special Feature highlights the essential role of public engagement in building trust, raising awareness and improving understanding in infectious disease research, control and prevention. In fields such as immunology, microbiology and vaccinology, public engagement ensures that scientific advances are both communicated and applied effectively for improved global health. The present collection of articles presents creative and inspiring approaches to achieve this, from gamification tools that make complex concepts accessible to community-led initiatives that strengthen vaccine confidence among marginalized groups. Together, these contributions reinforce that public engagement requires dialogue, co-creation and the inclusion of diverse perspectives in research and policy. To maximize impact, engagement must be embedded as a core element of academic research and teaching, backed by training, recognition and sustained support. By advocating to make public engagement integral to infectious disease research and preparedness, this Special Feature demonstrates how collaboration between scientists and society can build more resilient and responsive health systems.
