Allergic inflammation triggers dyslipidemia via IgG signalling.

BACKGROUND: Allergic diseases begin early in life and are often chronic, thus creating an inflammatory environment that may precede or exacerbate other pathologies. In this regard, allergy has been associated to metabolic disorders and with a higher risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. METHODS: We used a murine model of allergy and atherosclerosis, different diets and sensitization methods, and cell-depleting strategies to ascertain the contribution of acute and late phase inflammation to dyslipidemia. Untargeted lipidomic analyses were applied to define the lipid fingerprint of allergic inflammation at different phases of allergic pathology. Expression of genes related to lipid metabolism was assessed in liver and adipose tissue at different times post-allergen challenge. Also, changes in serum triglycerides (TGs) were evaluated in a group of 59 patients ≥14 days after the onset of an allergic reaction. RESULTS: We found that allergic inflammation induces a unique lipid signature that is characterized by increased serum TGs and changes in the expression of genes related to lipid metabolism in liver and adipose tissue. Alterations in blood TGs following an allergic reaction are independent of T-cell-driven late phase inflammation. On the contrary, the IgG-mediated alternative pathway of anaphylaxis is sufficient to induce a TG increase and a unique lipid profile. Lastly, we demonstrated an increase in serum TGs in 59 patients after undergoing an allergic reaction. CONCLUSION: Overall, this study reveals that IgG-mediated allergic inflammation regulates lipid metabolism.

Developmental perfluorooctane sulfonic acid exposure exacerbates house dust mite induced allergic responses in adult mice.

Perfluorooctane sulfonic acid (PFOS) is a long-chain per- and polyfluoroalkyl substance (PFAS), a persistent organic pollutant, which has been used in aqueous film-forming foams. Emerging epidemiological evidence indicates a significant body burden of PFOS is observed in the lungs. Furthermore, developmental PFOS exposure dysregulates lung development and exacerbates eosinophilic inflammation, which are critical risk factors for asthma. However, it is unknown whether PFOS exerts sex-dependent effects on house dust mite (HDM) induced asthmatic progression and allergic inflammation. In this study, timed pregnant Balb/cJ dams were dosed orally via PFOS (1.0 mg/kg/d) spiked or vehicle control mealworms from gestational day (GD) 0.5 to postnatal day (PND) 21. Subsequently, HDM (30 µg/day) was administered starting at PND 77-82 for 10 days, and the mice were sacrificed 48 h after their final treatment. The serum and lung PFOS concentrations were 3.391 ± 0.189 µg/mL and 3.567 ± 0.1676 µg/g in the offspring, respectively. Male mice exposed to PFOS + HDM showed higher total cell counts in bronchoalveolar lavage fluid (BALF), macrophage counts, and eosinophil counts compared to mice exposed to HDM alone. Female mice exposed to PFOS + HDM had increased BALF eosinophil percentage, mucous production, alternatively activated (M2) macrophage polarization, and M2-associated gene expression compared to female mice exposed to HDM alone. PFOS exposure had no significant effect on HDM-induced IL-4, IL-5, or IL-13, but RANTES was further elevated in female mice. Overall, our data suggest that developmental PFOS exposure increased the risk of exacerbated eosinophilic inflammation and M2 polarization, which were more severe in female mice, suggesting sex-dependent developmental effects of PFOS on allergic airway responses.

Stress Affects Mast Cell Proteases in Murine Skin in a Model of Atopic Dermatitis-like Allergic Inflammation.

Stress exposure worsens allergic inflammatory diseases substantially. Mast cells (MCs) play a key role in peripheral immune responses to neuroendocrine stress mediators such as nerve growth factor (NGF) and substance P (SP). Mast cell proteases (MCPs) and cholinergic factors (Chrna7, SLURP1) were recently described to modulate MC stress response. We studied MCPs and Chrna7/SLURP1 and their interplay in a mouse model for noise induced stress (NiS) and atopic dermatitis-like allergic inflammation (AlD) and in cultured MC lacking Chrna7. We found that the cholinergic stress axis interacts with neuroendocrine stress mediators and stress-mediator cleaving enzymes in AlD. SP-cleaving mMCP4+ MC were upregulated in AlD and further upregulated by stress in NiS+AlD. Anti-NGF neutralizing antibody treatment blocked the stress-induced upregulation in vivo, and mMCP4+ MCs correlated with measures of AlD disease activity. Finally, high mMCP4 production in response to SP depended on Chrna7/SLURP1 in cultured MCs. In conclusion, mMCP4 and its upstream regulation by Chrna7/SLURP1 are interesting novel targets for the treatment of allergic inflammation and its aggravation by stress.

Targeting NF-κB Signaling: Selected Small Molecules Downregulate Pro-Inflammatory Cytokines in Both Food Allergen and LPS-Induced Inflammation.

Although inflammation is primarily a protective response guarding the human body, it can result in a variety of chronic diseases such as allergies, auto-immune, cardiovascular diseases, and cancer. In NF-κB-mediated inflammation, many small molecules and food compounds characterized as nutraceuticals have shown positive effects associated with immunomodulatory properties. We investigated the effects of selected bioactive small molecules, commonly found in food components, vanillyl alcohol (VA) and lauric acid (LA), on different cell lines exposed to pro-inflammatory stimuli, lipopolysaccharide (LPS), and the food allergen actinidin (Act d 1). Pro-inflammatory cytokines were downregulated in response to both VA and LA, and this downregulation was caused by a decrease in the activation of the NF-κB pathway and the translocation of p65, the pathway's major component. Small nutraceutical molecules, VA and LA, showed not only inhibition of the pro-inflammatory cytokines, but also inhibition of the NF-κB activation, and reduced translocation of the p65 component. The present study may contribute to the therapeutic use of these molecules for various inflammatory diseases, which have in common an increased expression of pro-inflammatory cytokines and NF-κB-mediated inflammation.

TH2-driven manifestations of inborn errors of immunity.

Monogenic lesions in pathways critical for effector functions responsible for immune surveillance, protection against autoinflammation, and appropriate responses to allergens and microorganisms underlie the pathophysiology of inborn errors of immunity (IEI). Variants in cytokine production, cytokine signaling, epithelial barrier function, antigen presentation, receptor signaling, and cellular processes and metabolism can drive autoimmunity, immunodeficiency, and/or allergic inflammation. Identification of these variants has improved our understanding of the role that many of these proteins play in skewing toward TH2-related allergic inflammation. Early-onset or atypical atopic disease, often in conjunction with immunodeficiency and/or autoimmunity, should raise suspicion for an IEI. This becomes a diagnostic dilemma if the initial clinical presentation is solely allergic inflammation, especially when the prevalence of allergic diseases is becoming more common. Genetic sequencing is necessary for IEI diagnosis and is helpful for early recognition and implementation of targeted treatment, if available. Although genetic evaluation is not feasible for all patients with atopy, identifying atopic patients with molecular immune abnormalities may be helpful for diagnostic, therapeutic, and prognostic purposes. In this review, we focus on IEI associated with TH2-driven allergic manifestations and classify them on the basis of the affected molecular pathways and predominant clinical manifestations.

Aspalathin, a Primary Rooibos Flavonoid, Alleviates Mast Cell-Mediated Allergic Inflammation by the Inhibition of FcεRI Signaling Pathway.

Mast cells are primary cells initiating allergic inflammation by the release of various allergic mediators, such as histamine and pro-inflammatory cytokines. Aspalathin (ASP) is the predominant flavonoid found exclusively in rooibos, an herb that has been traditionally used in allergy relief therapy. In the present study, we investigated the beneficial effects of ASP on mast cell-mediated allergic inflammation. For in vivo study, two well-known mast cell-mediated local and systemic allergic inflammation mouse models were used: passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis mouse models (ASA). Oral administration of ASP dose-dependently suppressed immunoglobulin (Ig)E-mediated PCA responses evidenced by Evans blue extravasation, ear thickening, and mast cell degranulation. ASP also significantly mitigated ovalbumin-induced ASA responses, including hypothermia, histamine secretion, and the production of IgE and interleukin-4. Notably, ASP was more effective in suppressing allergic inflammation than nothofagin, another prominent flavonoid known as an anti-allergic component of rooibos. The regulatory mechanism of mast cell activation by ASP was clarified using mast cell line and primary cultured mast cells (RBL-2H3 and mouse bone marrow-derived mast cells). ASP reduced IgE-stimulated mast cells degranulation and intracellular calcium influx by the inhibition of FcεRI signaling pathway (Lyn, Fyn, and Syk). Moreover, ASP reduced pro-inflammatory cytokine expressions by inhibiting two major transcription factors, nuclear factor of activated T cells and nuclear factor-κB. Collectively, we proposed that ASP could be a potential therapeutic candidate for the treatment of mast cell-mediated allergic inflammatory diseases.

IL-24 promotes atopic dermatitis-like inflammation through driving MRSA-induced allergic responses.

Atopic dermatitis (AD) is a prevalent inflammatory skin disorder in which patients experience recurrent eczematous lesions and intense itching. The colonization of Staphylococcus aureus (S. aureus) is correlated with the severity of the disease, but its role in AD development remains elusive. Using single-cell RNA sequencing, we uncovered that keratinocytes activate a distinct immune response characterized by induction of Il24 when exposed to methicillin-resistant S. aureus (MRSA). Further experiments using animal models showed that the administration of recombinant IL-24 protein worsened AD-like pathology. Genetic ablation of Il24 or the receptor Il20rb in keratinocytes alleviated allergic inflammation and atopic march. Mechanistically, IL-24 acted through its heterodimeric receptors on keratinocytes and augmented the production of IL-33, which in turn aggravated type 2 immunity and AD-like skin conditions. Overall, these findings establish IL-24 as a critical factor for onset and progression of AD and a compelling therapeutic target.

Notch 2 signaling contributes to intestinal eosinophil adaptations in steady-state and tissue burden following oral allergen challenge.

Eosinophils function as inflammatory effectors in allergic diseases but also contribute to tissue homeostasis in steady state. Emerging data are revealing tissue eosinophils to be adaptive cells, imprinted by their local tissue microenvironment and exhibiting distinct functional phenotypes that may contribute to their homeostatic versus inflammatory capacities. However, signaling pathways that regulate eosinophil tissue adaptations remain elusive. Notch signaling is an evolutionarily conserved pathway that mediates differential cell fate programming of both pre- and post-mitotic immune cells. This study investigated a role for notch receptor 2 signaling in regulating eosinophil functions and tissue phenotype in both humans and mice. Notch 2 receptors were constitutively expressed and active in human blood eosinophils. Pharmacologic neutralization of notch 2 in ex vivo stimulated human eosinophils altered their activated transcriptome and prevented their cytokine-mediated survival. Genetic ablation of eosinophil-expressed notch 2 in mice diminished steady-state intestine-specific eosinophil adaptations and impaired their tissue retention in a food allergic response. In contrast, notch 2 had no effect on eosinophil phenotype or tissue inflammation within the context of allergic airways inflammation, suggesting notch 2-dependent regulation of eosinophil phenotype and function is specific to the gut. These data reveal notch 2 signaling as a cell-intrinsic mechanism that contributes to eosinophil survival, function, and intestine-specific adaptations. The notch 2 pathway may represent a viable strategy to reprogram eosinophil functional phenotypes in gastrointestinal eosinophil-associated diseases.

Keratinocyte-derived small extracellular vesicles supply antigens for CD1a-resticted T cells and promote their type 2 bias in the context of filaggrin insufficiency.

Introduction: Exosome-enriched small extracellular vesicles (sEVs) are nanosized organelles known to participate in long distance communication between cells, including in the skin. Atopic dermatitis (AD) is a chronic inflammatory skin disease for which filaggrin (FLG) gene mutations are the strongest genetic risk factor. Filaggrin insufficiency affects multiple cellular function, but it is unclear if sEV-mediated cellular communication originating from the affected keratinocytes is also altered, and if this influences peptide and lipid antigen presentation to T cells in the skin. Methods: Available mRNA and protein expression datasets from filaggrin-insufficient keratinocytes (shFLG), organotypic models and AD skin were used for gene ontology analysis with FunRich tool. sEVs secreted by shFLG and control shC cells were isolated from conditioned media by differential centrifugation. Mass spectrometry was carried out for lipidomic and proteomic profiling of the cells and sEVs. T cell responses to protein, peptide, CD1a lipid antigens, as well as phospholipase A2-digested or intact sEVs were measured by ELISpot and ELISA. Results: Data analysis revealed extensive remodeling of the sEV compartment in filaggrin insufficient keratinocytes, 3D models and the AD skin. Lipidomic profiles of shFLGsEV showed a reduction in the long chain (LCFAs) and polyunsaturated fatty acids (PUFAs; permissive CD1a ligands) and increased content of the bulky headgroup sphingolipids (non-permissive ligands). This resulted in a reduction of CD1a-mediated interferon-γ T cell responses to the lipids liberated from shFLG-generated sEVs in comparison to those induced by sEVs from control cells, and an increase in interleukin 13 secretion. The altered sEV lipidome reflected a generalized alteration in the cellular lipidome in filaggrin-insufficient cells and the skin of AD patients, resulting from a downregulation of key enzymes implicated in fatty acid elongation and desaturation, i.e., enzymes of the ACSL, ELOVL and FADS family. Discussion: We determined that sEVs constitute a source of antigens suitable for CD1a-mediated presentation to T cells. Lipids enclosed within the sEVs secreted on the background of filaggrin insufficiency contribute to allergic inflammation by reducing type 1 responses and inducing a type 2 bias from CD1a-restricted T cells, thus likely perpetuating allergic inflammation in the skin.

Gonadal sex and chromosome complement influence the gut microbiome in a mouse model of allergic airway inflammation.

Evidence abounds that gut microbiome components are associated with sex disparities in the immune system. However, it remains unclear whether the observed sex disparity in asthma incidence is associated with sex-dependent differences in immune-modulating gut microbiota, and/or its influence on allergic airway inflammatory processes. Using a mouse model of house dust mite (HDM)-induced allergic inflammation and the four core genotypes (FCGs) model, we have previously reported sex differences in lung inflammatory phenotypes. Here, we investigated associations of gut microbiomes with these phenotypes by challenging FCG mice [mouse with female sex chromosome and male gonad (XXM), mouse with female sex chromosome and female gonad (XXF), mouse with male sex chromosome and male gonad (XYM), and mouse with male sex chromosome and female gonad (XYF); n = 7/group] with HDM (25 µg) or PBS intranasally for 5 wk and collecting fecal samples. We extracted fecal DNA and analyzed the 16S microbiome via Targeted Metagenomic Sequencing. We compared α and ß diversity across genotypes and assessed the Firmicutes/Bacteroidetes (F/B) ratio. When comparing baseline and after exposure for the FCG, we found that the gut F/B ratio was only increased in the XXM genotype. We also found that α diversity was significantly increased in all FCG mice upon HDM challenge, with the highest increase in the XXF, and the lowest in the XXM genotypes. Similarly, ß diversity of the microbial community was also affected by challenge in a gonad- and chromosome-dependent manner. In summary, our results indicated that HDM treatment, gonads, and sex chromosomes significantly influence the gut microbial community composition. We concluded that allergic lung inflammation may be affected by the gut microbiome in a sex-dependent manner involving both hormonal and genetic influences.NEW & NOTEWORTHY Recently, the gut microbiome and its role in chronic respiratory disease have been the subject of extensive research and the establishment of its involvement in immune functions. Using the FCG mouse model, our findings revealed the influence of gonads and sex chromosomes on the microbial community structure before and after exposure to HDM. Our data provide a potential new avenue to better understand mediators of sex disparities associated with allergic airway inflammation.

Nur77 Mediates Anaphylaxis by Regulating miR-21a.

Nur77 belongs to the NR4A subfamily of orphan nuclear hormone receptors. It has been shown to play important roles in metabolism, cancer progression, cellular differentiation, and the regulation of immune process. However, there has yet to be research reporting on the role of Nur77 in allergic inflammations such as anaphylaxis. This study aimed to identify molecules that could mediate allergic inflammations. To this end, we performed RNA sequencing analysis employing bone marrow-derived mast cells (BMMCs). Antigen (DNP-HSA) stimulation increased the expression levels of transcription factors such as Nr4a3 (NOR1), Nr4a1 (Nur77), and Nr4a2 (Nurr1). We focused our study on Nur77. Antigen stimulation increased the expression of Nur77 in a time- and dose-dependent manner in rat basophilic leukemia cells (RBL2H3). The downregulation of Nur77 prevented both antigen-induced increase in ß-hexosaminidase activity as well as hallmarks of allergic reactions such as HDAC3, COX2, and MCP1 in RBL2H3 cells. Nur77 was necessary for both passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA). TargetScan analysis predicted that miR-21a would be a negative regulator of Nur77. miR-21a mimic negatively regulated PCA and PSA by inhibiting the hallmarks of allergic reactions. ChIP assays showed that c-JUN could bind to the promoter sequences of Nur77. Antigen stimulation increased the expression of c-JUN in RBL2H3 cells. Altogether, our findings demonstrate the regulatory role played by Nur77-miR-21a loop in allergic inflammations such as anaphylaxis, making this the first report to present the role played by Nur77 in an allergic inflammation. Our results suggest that Nur77 and miR-21 might serve as targets for developing anti-allergy drugs.

Involvement of Muscarinic M3 Receptor in the Development of M2 Macrophages in Allergic Inflammation.

INTRODUCTION: The muscarinic M3 receptor antagonist, tiotropium, has a bronchodilatory effect on asthma patients. Additionally, tiotropium inhibits allergic airway inflammation and remodeling in a murine asthma model. However, the underlying mechanisms of this M3 receptor antagonist remain unclear. Therefore, we investigated the effect of muscarinic M3 receptor blockage on M2 macrophage development during allergic airway inflammation. METHODS: BALB/c mice were sensitized and challenged with ovalbumin to develop a murine model of allergic airway inflammation mimicking human atopic asthma. During the challenge phase, mice were treated with or without tiotropium. Lung cells were isolated 24 h after the last treatment and gated using CD68-positive cells. Relm-α and Arginase-1 (Arg1) (M2 macrophage markers) expression was determined by flow cytometry. Mouse bone marrow mononuclear cell-derived macrophages (mBMMacs) and human peripheral blood mononuclear cells (PBMCs)-derived macrophages were stimulated with IL-4 and treated with a muscarinic M3 receptor antagonist in vitro. RESULTS: The total cells, eosinophils, and IL-5 and IL-13 levels in BAL fluids were markedly decreased in the asthma group treated with tiotropium compared to that in the untreated asthma group. The Relm-α and Arg1 expression in macrophages was reduced considerably in the asthma group treated with tiotropium compared to that in the untreated asthma group, suggesting that the development of M2 macrophages was inhibited by muscarinic M3 receptor blockage. Additionally, muscarinic M3 receptor blockage in vitro significantly inhibited M2 macrophage development in both mBMMacs- and PBMCs-derived macrophages. CONCLUSIONS: Muscarinic M3 receptor blockage inhibits M2 macrophage development and prevents allergic airway inflammation. Moreover, muscarinic M3 receptors might be involved in the differentiation of immature macrophages into M2 macrophages.

Downregulation of lncRNA CDKN2B-AS1 attenuates inflammatory response in mice with allergic rhinitis by regulating miR-98-5p/SOCS1 axis.

Long non-coding RNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) in various diseases has been verified. However, the underlying mechanism of CDKN2B-AS1 contributes to the development of allergic rhinitis (AR) remains unknown. To evaluate the impact of CDKN2B-AS1 on AR, BALB/c mice were sensitized by intraperitoneal injection of normal saline containing ovalbumin (OVA) and calmogastrin to establish an AR model. Nasal rubbing and sneezing were documented after the final OVA treatment. The concentrations of IgE, IgG1, and inflammatory elements were quantified using ELISA. Hematoxylin and eosin (H&E) staining and immunofluorescence were used to assess histopathological variations and tryptase expression, respectively. StarBase, TargetScan and luciferase reporter assays were applied to predict and confirm the interactions among CDKN2B-AS1, miR-98-5p, and SOCS1. CDKN2B-AS1, miR-98-5p, and SOCS1 levels were assessed by quantitative real-time PCR (qRT-PCR) or western blotting. Our results revealed that CDKN2B-AS1 was obviously over-expressed in the nasal mucosa of AR patients and AR mice. Down-regulation of CDKN2B-AS1 significantly decreased nasal rubbing and sneezing frequencies, IgE and IgG1 concentrations, and cytokine levels. Furthermore, down-regulation of CDKN2B-AS1 also relieved the pathological changes in the nasal mucosa, and the infiltration of eosinophils and mast cells. Importantly, these results were reversed by the miR-98-5p inhibitor, whereas miR-98-5p directly targeted CDKN2B-AS1, and miR-98-5p negatively regulated SOCS1 level. Our findings demonstrate that down-regulation of CDKN2B-AS1 improves allergic inflammation and symptoms in a murine model of AR through the miR-98-5p/SOCS1 axis, which provides new insights into the latent functions of CDKN2B-AS1 in AR treatment.

Novel insights into the anti-asthmatic effect of Raphanus sativus L. (Raphani Semen): Targeting immune cells, inflammatory pathways and oxidative stress markers.

ETHNOPHARMACOLOGICAL RELEVANCE: Raphanus sativus L. is a well-known medicinal plant with traditional therapeutic applications in various common ailments including inflammation and asthma. AIMS OF THE STUDY: This study aimed to evaluate the chemical composition and anti-asthmatic potential of the hydro-methanolic extract of the leaves of R. sativus L. (Rs.Cr) using various in vitro and in vivo investigations. MATERIALS AND METHODS: The Rs.Cr was subjected to preliminary phytochemical analysis and HPLC profiling. The safety was assessed through oral acute toxicity tests in mice. The antiasthmatic effect of the extract was studied using milk-induced leukocytosis and ovalbumin (OVA)-induced allergic asthma models established in mice. While mast cell degranulation and passive paw anaphylaxis models were established in rats. Moreover, effect of the extract was studied on various oxidative and inflammatory makers. The antioxidant effect of the extract was also studied by in vitro DPPH method. RESULTS: The HPLC profiling of Rs.Cr showed the presence of important polyphenols in a considerable quantity. In toxicity evaluation, Rs.Cr showed no sign of morbidity or mortality with LD50 < 2000 mg/kg. The extract revealed significant mast cell disruption in a dose-dependent manner compared to the intoxicated group. Similarly, treatment with Rs.Cr and dexamethasone significantly (p < 0.001) reduced paw edema volume. Subcutaneous injection of milk at a dose of 4 mL/kg, after 24 h of its administration, showed an increase in the leukocyte count in the intoxicated group. Similarly, mice treated with dexamethasone and Rs.Cr respectively showed a significant decrease in leukocytes and eosinophils count in the ovalbumin-induced allergic asthma model. The extract presented a significant (p˂0.001) alleviative effect on the levels of SOD and GSH, MDA, IL-4, IL-5, and IL-13 in a dose-dependent manner as compared to the intoxicated group. Furthermore, the histological evaluation also revealed a notable decrease in inflammatory and goblet cell count with reduced mucus production. CONCLUSION: The current study highlights mechanism-based novel insights into the anti-asthmatic potential of R. sativus that also strongly supports its traditional use in asthma.

Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond.

Signal transducer and activator of transcription (STAT)-6 is a transcription factor central to pro-allergic immune responses, although the function of human STAT6 at the whole-organism level has long remained unknown. Germline heterozygous gain-of-function (GOF) rare variants in STAT6 have been recently recognized to cause a broad and severe clinical phenotype of early-onset, multi-system allergic disease. Here, we provide an overview of the clinical presentation of STAT6-GOF disease, discussing how dysregulation of the STAT6 pathway causes severe allergic disease, and identifying possible targeted treatment approaches. Finally, we explore the mechanistic overlap between STAT6-GOF disease and other monogenic atopic disorders, and how this group of inborn errors of immunity (IEIs) powerfully inform our fundamental understanding of common human allergic disease.

Transcriptomics analysis of allergen-induced inflammatory gene expression in the Four-Core Genotype mouse model.

Sex differences in allergic inflammation have been reported, but the mechanisms underlying these differences remain unknown. Contributions of both sex hormones and sex-related genes to these mechanisms have been previously suggested in clinical and animal studies. Here, Four-Core Genotypes (FCG) mouse model was used to study the inflammatory response to house dust mite (HDM) challenge and identify differentially expressed genes (DEGs) and regulatory pathways in lung tissue. Briefly, adult mice (8-10 wk old) of the FCG (XXM, XXF, XYM, XYF) were challenged intranasally with 25 µg of HDM or vehicle (PBS-control group) 5 days/wk for 5 wk (n = 3/10 group). At 72 h after the last exposure, we analyzed the eosinophils and neutrophils in the bronchoalveolar lavage (BAL) of FCG mice. We extracted lung tissue and determined DEGs using Templated Oligo-Sequencing (TempO-Seq). DEG analysis was performed using the DESeq2 package and gene enrichment analysis was done using Ingenuity Pathway Analysis. A total of 2,863 DEGs were identified in the FCG. Results revealed increased eosinophilia and neutrophilia in the HDM-treated group with the most significantly expressed genes in XYF phenotype and a predominant effect of female hormones vs. chromosomes. Regardless of the sex hormones, mice with female chromosomes had more downregulated genes in the HDM group but this was reversed in the control group. Interestingly, genes associated with inflammatory responses were overrepresented in the XXM and XYF genotypes treated with HDM. Sex hormones and chromosomes contribute to inflammatory responses to HDM challenge, with female hormones exerting a predominant effect mediated by inflammatory DEGs.NEW & NOTEWORTHY Gene expression profiling helps to provide deep insight into the global view of disease-related mechanisms and responses to therapy. Using the Four-Core Genotype mouse model, our findings revealed the influence of sex hormones and sex chromosomes in the gene expression of lungs exposed to an aeroallergen (House Dust Mite) and identified sex-specific pathways to better understand sex disparities associated with allergic airway inflammation.

[Pathogenetic approach in the treatment of inflammatory diseases of the nose and paranasal sinuses]. / Patogeneticheskii podkhod v terapii vospalitel'nykh zabolevanii nosa i okolonosovykh pazukh.

In recent years, inflammatory diseases of the nose and paranasal sinuses have been on the rise. In addition to infectious diseases, in the modern world a large percentage of the population suffers from allergic diseases. The approach to therapy and the choice of a drug should take into account the pathogenesis of the inflammatory reaction in the nasal cavity and paranasal sinuses. By exerting its effect, the drug should reduce hyperemia and swelling of the nasal mucosa, reduce the level of mucus secretion, improve the drainage of the paranasal sinuses, i.e. possess vasoconstrictive and anti-allergic properties. As such a drug, you can use the combined intranasal spray Frinozol, which basically contains cetirizine and phenylephrine. The use of Frinozol in the complex treatment of inflammation of the mucous membrane of the nasal cavity and paranasal sinuses contributes to the rapid and pronounced weakening of the symptoms of the disease, and is also the key to successful therapy.

Topical Application of a PDE4 Inhibitor Ameliorates Atopic Dermatitis through Inhibition of Basophil IL-4 Production.

Phosphodiesterase 4 inhibitors have been approved for the treatment of atopic dermatitis. However, the cellular and molecular mechanisms underlying their therapeutic effect remain to be fully elucidated. In this study, we addressed this unsolved issue by analyzing the action of difamilast, a novel phosphodiesterase 4 inhibitor, on an oxazolone-induced skin allergic inflammation commonly used as a mouse model of atopic dermatitis. Topical application of difamilast ameliorated skin inflammation in association with reduced IL-4 expression even when the treatment commenced 4 days after the initiation of oxazolone challenge, showing its therapeutic effect on atopic dermatitis. IL-4-deficient mice displayed milder skin inflammation than did wild-type mice, and the difamilast treatment had little or no further therapeutic effect. This was also the case in mice depleted of basophils, predominant producers of IL-4 in the skin lesion, suggesting that difamilast may act on basophils. Notably, basophils accumulating in the skin lesion showed highly upregulated expression of Pde4b encoding the B subtype of the phosphodiesterase 4 family. Difamilast suppressed IL-4 production from basophils activated in vitro, at least in part, through inhibition of ERK phosphorylation. Taken together, difamilast appeared to ameliorate atopic dermatitis inflammation through the suppression of basophil IL-4 production in the skin lesion.

The Role of Diet and Nutrition in Allergic Diseases.

Allergic diseases are a set of chronic inflammatory disorders of lung, skin, and nose epithelium characterized by aberrant IgE and Th2 cytokine-mediated immune responses to exposed allergens. The prevalence of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis, has increased dramatically worldwide in the past several decades. Evidence suggests that diet and nutrition play a key role in the development and severity of allergic diseases. Dietary components can differentially regulate allergic inflammation pathways through host and gut microbiota-derived metabolites, therefore influencing allergy outcomes in positive or negative ways. A broad range of nutrients and dietary components (vitamins A, D, and E, minerals Zn, Iron, and Se, dietary fiber, fatty acids, and phytochemicals) are found to be effective in the prevention or treatment of allergic diseases through the suppression of type 2 inflammation. This paper aims to review recent advances in the role of diet and nutrition in the etiology of allergies, nutritional regulation of allergic inflammation, and clinical findings about nutrient supplementation in treating allergic diseases. The current literature suggests the potential efficacy of plant-based diets in reducing allergic symptoms. Further clinical trials are warranted to examine the potential beneficial effects of plant-based diets and anti-allergic nutrients in the prevention and management of allergic diseases.