Effect of biologic therapies on quality of life in severe asthma: Findings from the PRISM study.

Background: Anti-type 2 (T2) biologic therapies (biologics) improve exacerbation rates, lung function, and asthma-related quality of life (QoL) in patients with severe T2 asthma. However, studies comparing different biologics are lacking. We evaluated the QoL in patients with severe asthma comprehensively and compare the efficacy of different T2-directed biologics using QoL questionnaires. Methods: We compared the QoL between severe and mild-to-moderate asthma and between severe asthma with and without biologics treatment. Data of mild-to-moderate were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea, and data of severe asthma were collected from the Precision Medicine Intervention in Severe Asthma. We included 183 patients with severe asthma treated with T2 biologics or conventional therapy between April 2020 and May 2021 and assessed QoL of them using the Questionnaire for Adult Korean Asthmatics (QLQAKA), Severe Asthma Questionnaire (SAQ), and EuroQoL-5Dimensions (EQ-5D) at baseline and 6 months. Results: The EQ-5D index (0.803) of severe asthma was lower than that of other chronic diseases representing a worse QoL. The scores for all questions of QLQAKA, except "cough," were lower (less control) in the severe asthma group than in the mild-to-moderate asthma group at baseline and 6 months (P < 0.05). The total scores and subscores of all domains of the QLQAKA, SAQ, and EQ-5D improved significantly 6 months after biologic therapy but not after conventional therapy. The total QLQAKA, SAQ, and EQ-5D scores improved after 6 months in the anti-IL-5 (P < 0.05) and anti-IL-4/IL-13 (P < 0.05) treatment groups with no significant difference between groups (P > 0.05). Conclusion: QoL was worse in severe asthma than in mild-to-moderate asthma and other chronic diseases. T2 biologics equally improved QoL in patients with severe asthma.

6-gingerol and its derivatives inhibit Helicobacter pylori-induced gastric mucosal inflammation and improve gastrin and somatostatin secretion.

The resistance of Helicobacter pylori (H. pylori) has increased in recent years, prompting a trend in the research and development of new drugs. In our study, three derivatives (JF-1, JF-2, and JF-3) were synthesized using 6-gingerol as the main component, while JF-4, containing both 6-gingerol and 6-shogaol as the main components, was extracted from dried ginger. The minimum inhibitory concentrations (MICs), determined using the ratio dilution method, were 80 µg/mL for JF-1, 40 µg/mL for JF-2, 30 µg/mL for JF-3, 40 µg/mL for JF-4, 60 µg/mL for 6-gingerol standard (SS), and 0.03 µg/mL for amoxicillin (AMX). After treating H. pylori-infected mice, the inflammation of the gastric mucosa was suppressed. The eradication rate of H. pylori was 16.7% of JF-3 low-dose treatment (LDT), 25.0% of JF-3 high-dose treatment (HDT), 16.7% of JF-4 LDT, 16.7% of JF-4 HDT, 30% of SS LDT, 50% of SS HDT, and 36.4% of the positive control group (PCG). The levels of gastrin, somatostatin (SST), IFN-γ, IL-4, and IL-8 were significantly recovered in the JF-3 and JF-4 administration groups, but the effect was stronger in the high-dose group. These results demonstrate that 6-gingerol and its derivatives have significant anti-Helicobacter pylori effects and are promising potential treatments for H. pylori infection.

Productions of Th2 cytokines, IL-4 and IL-10, were enhanced via the function of IL-2 from anti-CD3 antibody-stimulated mouse spleen cells treated with caffeic acid phenethyl ester.

OBJECTIVES: Interleukin (IL)-2 production by mouse spleen cells stimulated with an anti-CD3 antibody is significantly enhanced by caffeic acid phenethyl ester (CAPE), a major constituent of Chinese propolis (CP). In this study, we evaluated the functional significance of IL-2 in CAPE-treated activated spleen cells. METHODS: Mouse spleen cells were stimulated with an anti-CD3 monoclonal antibody in the presence of CAPE. Cytokine production was examined using an enzyme-linked immunosorbent assay (ELISA). Messenger RNA level expression was examined via reverse transcription quantitative polymerase chain reaction (RT-PCR). IL-2 function was assessed using IL-2 and a neutralizing antibody. Spleen cell subsets were identified and characterized using flow cytometry. RESULTS: CAPE treatment of anti-CD3 antibody-stimulated spleen cells reduced IFN-γ production, then enhanced IL-2 production, followed by enhancement of IL-4 and IL-10 production. The Th2 cytokine production enhancing effects of CAPE were completely abolished by addition of an anti-IL-2 neutralizing antibody. In the absence of CAPE, exogenously added IL-2 could enhance IL-4 production to a lesser degree, but did not stimulate IL-10 production, in stimulated spleen cells. Interestingly, CAPE significantly reduced the proportions of CD4+ and CD8+ cells, and increased those of CD4-CD8- cells among anti-CD3 stimulated spleen cells, in the presence or absence of anti-IL-2 neutralizing antibody treatment. CONCLUSIONS: CAPE reduced IFN-γ production, then enhanced IL-4 and IL-10 production via the activity of specifically elevated IL-2 in stimulated spleen cells. CAPE exerted these effects in a CD4- CD8- cell specific manner.

Cell-Specific Contribution of IL4 Receptor α Signaling Shapes the Overall Manifestation of Allergic Airway Disease.

IL-4 and IL-13 play a critical role in allergic asthma pathogenesis via their common receptor, i.e., IL4Rα. However, the cell-specific role of IL4Rα in mixed allergens (MA)-induced allergic asthma has remained unclear. Therefore, we aimed to identify the cell-specific contribution of IL4Rα signaling in the manifestation of various pathological outcomes in mice with allergic airway disease. We compared MA-induced pathological outcomes between hematopoietic progenitor cells (HPCs)- or non-HPCs-specific IL4Rα-deficient chimera, myeloid cell-specific IL4Rα-deficient (LysMcre+/+/IL4Rαfl/fl), and airway epithelial cell-specific IL4Rα-deficient (CCSP-Cre+ /IL4Rαfl/fl) mice. Chimeric mice with systemic IL4Rα sufficiency displayed hallmark features of allergic asthma, including eosinophilic and lymphocytic infiltration, type 2 (Th2) cytokine/chemokine production, IgE production, and lung pathology. These features were markedly reduced in chimeric mice with systemic IL4Rα deficiency. Non-HPCs-specific IL4Rα-deficient mice displayed typical inflammatory features of allergic asthma but with markedly reduced mucous cell metaplasia (MCM). Deletion of IL4Rα signaling on airway epithelial cells, a subpopulation within the non-HPC lineage, resulted in almost complete absence of MCM. In contrast, all features of allergic asthma except for MCM and mucin production were mitigated in HPCs-specific IL4Rα-deficient chimeric mice. Deleting IL4Rα signaling in myeloid cells, a subpopulation within the HPC lineage, significantly alleviated MA-induced allergic airway inflammatory responses, but similar to the HPCs-specific IL4Rα-deficient chimeric mice, these mice showed significant MCM and mucin production. Our findings demonstrate that the differential allergen responsiveness seen in mice with HPCs-specific and non-HPCs-specific IL4Rα deficiency is predominantly driven by the absence of IL4Rα in myeloid cells and airway epithelial cells, respectively. Our findings also highlight distinct and mutually exclusive roles of IL4Rα signaling in mediating pathological outcomes within the myeloid and airway epithelial cell compartments.

TRAF3 regulates STAT6 activation and T helper cell differentiation by modulating the phosphatase PTP1B.

The adaptor protein TNFR associated factor 3 (TRAF3) is a multifaceted regulator of lymphocyte biology that plays key roles in modulation of the molecular signals required for T cell activation and function. TRAF3 regulates signals mediated by the T cell receptor (TCR), costimulatory molecules, and cytokine receptors, which each drive activation of the serine/threonine kinase Akt. The impact of TRAF3 upon TCR/CD28-mediated activation of Akt, and thus on the diverse cellular processes regulated by Akt, including CD4 T cell fate decisions, remains poorly understood. We show here that TRAF3 deficiency led to impaired Akt activation, and thus to impaired in vitro skewing of CD4 T cells into the TH1 and TH2 fates. We investigated the role of TRAF3 in regulation of signaling pathways that drive TH1 and TH2 differentiation, and found that TRAF3 enhanced activation of Signal transducer and activator of transcription 6 (STAT6), thus promoting skewing toward the TH2 fate. TRAF3 promoted STAT6 activation by regulating recruitment of the inhibitory molecule Protein tyrosine phosphatase 1B (PTP1B) to the IL-4R signaling complex, in a manner that required integration of TCR/CD28- and IL-4R-mediated signals. This work reveals a new mechanism for TRAF3-mediated regulation of STAT6 activation in CD4 T cells, and adds to our understanding of the diverse roles played by TRAF3 as an important regulator of T cell biology.

Aloe-emodin alleviates inflammatory bowel disease in mice by modulating intestinal microbiome homeostasis via the IL-4/IL-13 axis.

Introduction: Inflammatory bowel disease (IBD) is a global health concern. Aloe-emodin (AE) has diverse pharmacological benefits, including anti-inflammatory effects. However, its role in IBD remains unclear, prompting our investigation of its regulatory effects and mechanisms in an IBD mouse model. Methods: We studied the therapeutic efficacy of AE in alleviating symptoms and modulating cytokine secretion in a murine model of dextran sulfate sodium (DSS)-induced colitis. BALB/c mice were administered DSS to induce colitis and were subsequently treated with varying doses of AE. Changes in body weight, fecal lipocalin-2 (LCN2) levels, colon tissue histology, and serum cytokine concentrations were evaluated to assess the effects of AE treatment. Additionally, 16 S rRNA sequencing was used to analyze alterations in the composition of the gut microbiota following AE intervention. Finally, the database was used to analyze the signaling pathways associated with IBD in AE and to detect the expression levels of interleukin (IL)-4 pathway using real-time quantitative reverse transcription PCR. Exogenous IL-4 was used in rescue experiments to observe its effects on the disease process of IBD under AE regulation. Results: AE treatment resulted in a dose-dependent mitigation of weight loss, reduction in fecal LCN2 levels, and amelioration of histological damage in DSS-induced colitis in mice. The levels of superoxide dismutase and catalase increased, whereas malondialdehyde decreased following AE treatment, indicating a dose-dependent alleviation of colitis symptoms. Furthermore, AE administration attenuated the secretion of pro-inflammatory cytokines, including IL-17, tumor necrosis factor-alpha (TNF-α), and chemokine ligand 1, while promoting the expression of anti-inflammatory cytokines IL-4 and IL-13. Analysis of the gut microbiota revealed that AE effectively suppressed the overgrowth of colitis-associated bacterial species and restored microbial homeostasis. Finally, we found that overexpression of IL-4 was able to reverse the therapeutic effect of AE for DSS-induced IBD. Conclusion: AE shows promise in alleviating colitis severity, influencing inflammatory cytokines, and modulating the gut microbiota in an IBD mouse model via the IL-4/IL-13 pathway, suggesting its potential as a natural IBD remedy.

Leukemia inhibitory factor drives transcriptional programs that promote lipid accumulation and M2 polarization in macrophages.

Leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, plays a central role in homeostasis and disease. Interestingly, some of the pleiotropic effects of LIF have been attributed to the modulation of macrophage functions although the molecular underpinnings have not been explored at a genome-wide scale. Herein, we investigated LIF-driven transcriptional changes in murine bone marrow-derived macrophages (BMDM) by RNA-seq. In silico analyses revealed a selective and time-dependent remodelling of macrophage gene expression programs associated with lipid metabolism and cell activation. Accordingly, a subset of LIF-upregulated transcripts related to cholesterol metabolism and lipid internalization was validated by RT-qPCR. This was accompanied by a LIF-enhanced capacity for lipid accumulation in macrophages upon incubation with oxidated low-density lipoprotein (Ox-LDL). Mechanistically, LIF triggered the phosphorylation (Y705 and S727) and nuclear translocation of the transcription factor STAT3 in BMDM. Consistent with this, Ingenuity Pathway Analysis (IPA) identified STAT3 as an upstream regulator of a subset of transcripts, including Il4ra, in LIF-treated macrophages. Notably, LIF priming enhanced BMDM responses to IL-4-mediated M2 polarization (i.e., increased arginase activity and accumulation of transcripts encoding for M2 markers). Conversely, LIF stimulation had no significant effect in BMDM responses to M1 polarizing stimuli (IFNγ and LPS). Thus, our study provides insight into the transcriptional landscape of LIF-treated macrophages, shedding light on its role in lipid metabolism and M2 polarization responses. A better understanding of the regulatory mechanisms governing LIF-driven changes might help informing novel therapeutic approaches aiming to reprogram macrophage phenotypes in diseased states (e.g., cancer, atherosclerosis, infection, etc.).

Do aluminum, boron, arsenic, cadmium, lipoperoxidation, and genetic polymorphism determine male fertility?

Male infertility is a world multifactorial problem modulated by environmental and genetic factors. Male aspects account for 20-50 % of infertility cases. Our results are unique because they treat the importance of components participating in the determination of male infertility (environmental and immunogenetic determinants, seminological analysis, lipoperoxidation, genetic determinants, role of aluminum, arsenic, cadmium and boron). We analyzed agents affecting male reproductive potential (aluminum, boron, cadmium, arsenic, lipid peroxidation, gene polymorphisms (MTHFRv.C677T (rs1801133) (chromosome-1) and IL-4v.C589T (rs2243250) (chromosome-5) in men with semen disorders (n=76) and with normozoospermia (n=87) from Central Poland. Polymorphisms of MTHFRv.C677T and IL-4v.C589T genes indirectly shape toxic metals concentration and lipoperoxidation but do not exert direct influence on male fertility disorders (monomorphism and lack of differences in genotypes frequency). Men with genotype TT or CC (IL-4v.C589T) show some differentiation in elements concentration and intensity of lipoperoxidation. Analysis of TT or CC (IL-4v.C589T) genotype brought correlations with B, Al, Cd, and lipoperoxidation (P<0.05) and suggesting that mentioned factors jointly shape male reproductive capability. Toxic metals may play an important role in shaping of men genetic polymorphisms, since Cd was identified as a factor increasing risk of qualification to infertile group, predisposing to fertility disorders. B, Al and Cd may be considered as important modulators of reproductive condition. However, lipoperoxidation as an isolated predictive parameter does not produce convincing results in male reproductive potential (higher MDA concentration in healthy men). Our results may be helpful in the diagnosis of male infertility, in the reduction of idiopathic cases of unknown origin and in implementation of targeted and more effective treatment (pharmacological, hormonal). Identification of environmental stressors and their correlations with fertility disorders can help to eliminate or reduce the impact of factors unfavorable to fertility. Our results highlight the importance of environmental and immunogenetic factors in shaping of defensive potential against destruction of spermatozoa and infer a role of oxidative stress in the induction of gene polymorphisms, affecting male fertility.

Systematic review of dupilumab safety and efficacy for treatment of keloid scars.

Keloids, characterized by excessive scar formation following dermal inflammation, pose a therapeutic challenge due to high recurrence rates. Radiation therapy, contraindicated in children, can minimize recurrence post-surgical removal. Dupilumab, which inhibits the pro-fibrotic interleukin-4/interleukin-13 axis, may effectively manage keloids when intralesional corticosteroid injections are unsuccessful. It may also prevent recurrence post-surgery in pediatric patients. This systematic review assesses the efficacy and safety of dupilumab for the treatment of keloids. Through a systematic search adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we identified and analyzed outcomes from three case reports and three case series studies, totaling 15 patients. Results indicate variable responses to treatment, including significant improvements, no clinical change, and worsening of keloid symptoms. Additional research is needed to recommend using dupilumab to treat keloids (Grade D). Treatment response variability may be linked to differences in interleukin-4/interleukin-13 activity between active and inactive keloids. Additionally, the unintended promotion of T helper 17 cell differentiation by dupilumab may worsen keloids.

The JAK1/JAK2 inhibitor ruxolitinib inhibits mediator release from human basophils and mast cells.

Introduction: The Janus kinase (JAK) family includes four cytoplasmic tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) constitutively bound to several cytokine receptors. JAKs phosphorylate downstream signal transducers and activators of transcription (STAT). JAK-STAT5 pathways play a critical role in basophil and mast cell activation. Previous studies have demonstrated that inhibitors of JAK-STAT pathway blocked the activation of mast cells and basophils. Methods: In this study, we investigated the in vitro effects of ruxolitinib, a JAK1/2 inhibitor, on IgE- and IL-3-mediated release of mediators from human basophils, as well as substance P-induced mediator release from skin mast cells (HSMCs). Results: Ruxolitinib concentration-dependently inhibited IgE-mediated release of preformed (histamine) and de novo synthesized mediators (leukotriene C4) from human basophils. Ruxolitinib also inhibited anti-IgE- and IL-3-mediated cytokine (IL-4 and IL-13) release from basophils, as well as the secretion of preformed mediators (histamine, tryptase, and chymase) from substance P-activated HSMCs. Discussion: These results indicate that ruxolitinib, inhibiting the release of several mediators from human basophils and mast cells, is a potential candidate for the treatment of inflammatory disorders.

Stromal cell and B cell dialogue potentiates IL-33-enriched lymphoid niches to support eosinophil recruitment and function during type 2 immunity.

Eosinophils are involved in host protection against multicellular organisms. However, their recruitment to the mesenteric lymph node (mLN) during type 2 immunity is understudied. Our results demonstrate that eosinophil association with lymphoid stromal niches constructed by fibroblastic reticular cells (FRCs) and lymphatic endothelial cells is diminished in mice selectively lacking interleukin (IL)-4Rα or lymphotoxin-ß (LTß) expression on B cells. Furthermore, eosinophil survival, activation, and enhanced Il1rl1 receptor expression are driven by stromal cell and B cell dialogue. The ligation of lymphotoxin-ß receptor (LTßR) on FRCs improves eosinophil survival and significantly augments IL-33 expression and eosinophil homing to the mLN, thus confirming the significance of lymphotoxin signaling for granulocyte recruitment. Eosinophil-deficient ΔdblGATA-1 mice show diminished mLN expansion, reduced interfollicular region (IFR) alarmin expression, and delayed helminth clearance, elucidating their importance in type 2 immunity. These findings provide insight into dialogue between stromal cells and B cells, which govern mLN eosinophilia, and the relevance of these mechanisms during type 2 immunity.

Pharmacological Trends in the Management of Atopic Dermatitis: A Comprehensive Review.

Atopic dermatitis (AD) is a prevalent, chronic inflammatory skin condition characterized by pruritus, erythema, and impaired skin barrier function. AD management presents significant challenges due to its complex pathophysiology involving immune dysregulation and genetic predispositions. While traditional therapies, such as topical corticosteroids and emollients, remain foundational, their limitations have spurred the development of novel pharmacological approaches. This comprehensive review explores current pharmacological trends in the management of AD, focusing on emerging therapies that target specific immunological pathways. Biologic agents, including monoclonal antibodies against interleukin (IL)-4, IL-13, and IL-31 receptors, offer targeted mechanisms to modulate immune responses implicated in AD pathogenesis. Janus kinase (JAK) and phosphodiesterase-4 (PDE-4) inhibitors represent another class of promising therapies, providing alternatives for patients resistant to conventional treatments. The review synthesizes evidence from clinical trials and studies to evaluate these pharmacological agents' efficacy and safety profiles. Considerations for personalized medicine approaches, including biomarkers for treatment response prediction and genotype-based therapies, are discussed to highlight the potential for tailored treatment strategies in AD management. In conclusion, this review underscores the evolving landscape of pharmacological interventions for AD, emphasizing the need for continued research to address unmet clinical needs and optimize patient outcomes. By delineating current advancements and future directions, this review aims to inform clinical practice and guide future research endeavours in dermatology.

Involvement of M2 macrophages polarization in PM2.5-induced COPD by upregulating MMP12 via IL4/STAT6 pathway.

Biomass-related airborne fine particulate matter (PM2.5) is an important risk factor for chronic obstructive pulmonary disease (COPD). Macrophage polarization has been reported to be involved in PM2.5-induced COPD, but the dynamic characteristics and underlying mechanism of this process remain unclear. Our study established a PM2.5-induced COPD mouse model and revealed that M2 macrophages predominantly presented after 4 and 6 months of PM2.5 exposure, during which a notable increase in MMP12 was observed. Single cell analysis of lung tissues from COPD patients and mice further revealed that M2 macrophages were the dominant macrophage subpopulation in COPD, with MMP12 being involved as a hub gene. In vitro experiments further demonstrated that PM2.5 induced M2 polarization and increased MMP12 expression. Moreover, we found that PM2.5 increased IL-4 expression, STAT6 phosphorylation and nuclear translocation. Nuclear pSTAT6 then bound to the MMP12 promoter region. Furthermore, the inhibition of STAT6 phosphorylation effectively abrogated the PM2.5-induced increase in MMP12. Using a coculture system, we observed a significantly reduced level of E-cadherin in alveolar epithelial cells cocultured with PM2.5-exposed macrophages, while the decrease in E-cadherin was reversed by the addition of an MMP12 inhibitor to the co-culture system. Taken together, these findings indicated that PM2.5 induced M2 macrophage polarization and MMP12 upregulation via the IL-4/STAT6 pathway, which resulted in alveolar epithelial barrier dysfunction and excessive extracellular matrix (ECM) degradation, and ultimately led to COPD progression. These findings may help to elucidate the role of macrophages in COPD, and suggest promising directions for potential therapeutic strategies.

Diterpenoid DGT alleviates atopic dermatitis-like responses in vitro and in vivo via targeting IL-4Rα.

BACKGROUND: Atopic dermatitis is a common chronic inflammatory skin disease characterized by relapsing eczema and intense itch. DGT is a novel synthetic heterocyclic diterpenoid derived from plants. Its therapeutic potential and mechanism(s) of action are poorly understood. OBJECTIVES: We investigated the potent therapeutic effect of DGT on atopic dermatitis, exploring the underlying mechanisms and determining whether DGT is a safe and well-tolerated topical treatment. METHODS: We observed anti-inflammatory effects of DGT on tumor necrosis factor-α/interferon-γ-treated human keratinocytes, and anti-allergic effects on immunoglobulin E-sensitized bone marrow-derived mast cells. In vivo, DGT was topically applied to two experimental mouse models of atopic dermatitis: oxazolone-induced sensitization and topically applied calcipotriol. Then the therapeutic effects of DGT were evaluated physiologically and morphologically. Moreover, we performed nonclinical toxicology and safety pharmacology research, including general toxicity, pharmacokinetics, and safety pharmacology on the cardiovascular, respiratory, and central nervous systems. RESULTS: In keratinocytes, DGT reduced the expression of inflammatory factors, promoting the expression of barrier functional proteins and tight junctions and maintaining the steady state of barrier function. DGT also inhibited the activation and degranulation of mast cells induced by immunoglobulin E. Moreover, we found that interleukin-4 receptor-α was the possible target of DGT. Meanwhile, DGT had therapeutic effects on oxazolone/calcipotriol-treated mice. Notably, our pharmacology results demonstrated that DGT was safe and nontoxic in our studies. CONCLUSION: DGT's potent anti-inflammatory effects and good safety profile suggest that it is a potential candidate for the treatment of atopic dermatitis.

Targeting amino acid-metabolizing enzymes for cancer immunotherapy.

Despite the immune system's role in the detection and eradication of abnormal cells, cancer cells often evade elimination by exploitation of various immune escape mechanisms. Among these mechanisms is the ability of cancer cells to upregulate amino acid-metabolizing enzymes, or to induce these enzymes in tumor-infiltrating immunosuppressive cells. Amino acids are fundamental cellular nutrients required for a variety of physiological processes, and their inadequacy can severely impact immune cell function. Amino acid-derived metabolites can additionally dampen the anti-tumor immune response by means of their immunosuppressive activities, whilst some can also promote tumor growth directly. Based on their evident role in tumor immune escape, the amino acid-metabolizing enzymes glutaminase 1 (GLS1), arginase 1 (ARG1), inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and interleukin 4 induced 1 (IL4I1) each serve as a promising target for immunotherapeutic intervention. This review summarizes and discusses the involvement of these enzymes in cancer, their effect on the anti-tumor immune response and the recent progress made in the preclinical and clinical evaluation of inhibitors targeting these enzymes.

IL-4-induced SOX9 confers lineage plasticity to aged adult lung stem cells.

Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease.

Collagen extracellular matrix promotes gastric cancer immune evasion by activating IL4I1-AHR signaling.

BACKGROUND: Gastric cancer (GC) remains a significant global health challenge with poor prognosis, partly due to its ability to evade the immune system. The extracellular matrix (ECM), particularly collagen, plays a crucial role in tumor immune evasion, but the underlying mechanisms are not fully understood. This study investigates the role of collagen ECM in promoting immune evasion in gastric cancer by activating the IL4I1-AHR signaling pathway. METHODS: We cultured gastric cancer cells in 3D collagen gels and assessed their immune evasion capabilities by co-culturing with HER2-specific CAR-T cells. The expression of IL4I1 and its metabolites was analyzed, and the role of integrin αvß1 in mediating the effects of collagen was explored. Additionally, the impact of IL4I1-induced AHR activation on CAR-T cell exhaustion was evaluated, both in vitro and in vivo. RESULTS: We found that gastric cancer cells cultured on collagen exhibited increased resistance to CAR-T cell cytotoxicity, which was associated with upregulated immune checkpoint molecules and downregulated effector cytokines on CAR-T cells. This was linked to increased IL4I1 expression, which was further induced by integrin αvß1 signaling within the 3D collagen environment. IL4I1 metabolites, particularly KynA, promoted CAR-T cell exhaustion by activating the AHR pathway, leading to decreased cytotoxicity and tumor growth inhibition. CONCLUSIONS: Our study reveals a novel mechanism by which the collagen ECM facilitates immune evasion in gastric cancer through the activation of IL4I1-AHR signaling, contributing to CAR-T cell exhaustion. Targeting this pathway could potentially enhance the efficacy of CAR-T cell therapy in gastric cancer.

Blocking the IL-4/IL-13 Axis versus the JAK/STAT Pathway in Atopic Dermatitis: How Can We Choose?

Atopic dermatitis (AD) is an immune-mediated skin disorder with a chronic-relapsing course and a multifactorial pathogenesis. In contrast to the traditional concept of AD as solely a type 2 immune-activated disease, new findings highlight the disease as highly heterogeneous, as it can be classified into variable phenotypes based on clinical/epidemiological or molecular parameters. For many years, the only therapeutic option for moderate-severe AD was traditional immunosuppressive drugs. Recently, the area of systemic therapy of AD has significantly flourished, and many new substances are now marketed, licensed, or in the last step of clinical development. Biological agents and small molecules have enriched the therapeutic armamentarium of moderate-to-severe AD, such as dupilumab, tralokinumab, lebrikizumab (monoclonal antibodies targeting the IL-4/13 pathway), abrocitinib, upadacitinib, and baricitinib (JAK inhibitors). Indeed, the AD treatment paradigm is now split into two main approaches: targeting the IL-4/13 axis or the JAK/STAT pathway. Both approaches are valid and have strong evidence of preclinical and clinical efficacy. Therefore, the choice between the two can often be difficult and represents a major challenge for dermatologists. Indeed, several important factors must be taken into account, such as the heterogeneity of AD and its classification in phenotypes, patients' comorbidities, age, and personal preferences. The aim of our review is to provide an overview of the clinical and molecular heterogeneities of AD and to explore the factors and parameters that, in clinical practice, may help inform clinical decision-making.

Type 2 severe asthma: pathophysiology and treatment with biologics.

INTRODUCTION: The hallmark of most patients with severe asthma is type 2 inflammation, driven by innate and adaptive immune responses leading to either allergic or non-allergic eosinophilic infiltration of airways. The cellular and molecular pathways underlying severe type 2 asthma can be successfully targeted by specific monoclonal antibodies. AREAS COVERED: This review article provides a concise overview of the pathophysiology of type 2 asthma, followed by an updated appraisal of the mechanisms of action and therapeutic efficacy of currently available biologic treatments used for management of severe type 2 asthma. Therefore, all reported information arises from a wide literature search performed on PubMed. EXPERT OPINION: The main result of the recent advances in the field of anti-asthma biologic therapies is the implementation of a personalized medicine approach, aimed to achieve clinical remission of severe asthma. Today this accomplishment is made possible by the right choice of the most beneficial biologic drug for the pathologic traits characterizing each patient, including type 2 severe asthma and its comorbidities.

Multiomics analysis identified IL-4-induced IL1RL1high eosinophils characterized by prominent cysteinyl leukotriene metabolism.

BACKGROUND: Clinical studies have demonstrated that IL-4, a type 2 cytokine, plays an important role in the pathogenesis of chronic rhinosinusitis and eosinophilic asthma. However, the direct effect of IL-4 on eosinophils remains unclear. OBJECTIVE: We aimed to elucidate the inflammatory effects of IL-4 on the functions of human eosinophils. METHODS: A multiomics analysis comprising transcriptomics, proteomics, lipidomics, quantitative RT-PCR, and flow cytometry was performed by using blood eosinophils from healthy subjects stimulated with IL-4, IL-5, or a combination thereof. RESULTS: Transcriptomic and proteomic analyses revealed that both IL-4 and IL-5 upregulate the expression of γ-gultamyl transferase 5, a fatty acid-metabolizing enzyme that converts leukotriene C4 into leukotriene D4. In addition, IL-4 specifically upregulates the expression of IL-1 receptor-like 1 (IL1RL1), a receptor for IL-33 and transglutaminase-2. Additional transcriptomic analysis of cells stimulated with IL-13 revealed altered gene expression profiles, characterized by the upregulation of γ-gultamyl transferase 5, transglutaminase-2, and IL1RL1. The IL-13-induced changes were not totally different from the IL-4-induced changes. Lipidomic analysis revealed that IL-5 and IL-4 additively increased the extracellular release of leukotriene D4. In vitro experiments revealed that STAT6 and IL-4 receptor-α control the expression of these molecules in the presence of IL-4 and IL-13. Analysis of eosinophils derived from patients with allergic disorders indicated the involvement of IL-4 and IL-13 at the inflamed sites. CONCLUSIONS: IL-4 induces the proallergic phenotype of IL1RL1high eosinophils, with prominent cysteinyl leukotriene metabolism via STAT6. These cellular changes represent potential therapeutic targets for chronic rhinosinusitis and eosinophilic asthma.