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    mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation. Sinclair Charles,Bommakanti Gayathri,Gardinassi Luiz,Loebbermann Jens,Johnson Matthew Joseph,Hakimpour Paul,Hagan Thomas,Benitez Lydia,Todor Andrei,Machiah Deepa,Oriss Timothy,Ray Anuradha,Bosinger Steven,Ravindran Rajesh,Li Shuzhao,Pulendran Bali Science (New York, N.Y.) Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that mechanistic target of rapamycin (mTOR)-dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for dendritic cell (DC) homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103 DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic T helper cell 2 (T2) to neutrophilic T17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DCs, which produced interleukin-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation. 10.1126/science.aaj2155
    TNF-α-induced protein 3 levels in lung dendritic cells instruct T2 or T17 cell differentiation in eosinophilic or neutrophilic asthma. Vroman Heleen,Bergen Ingrid M,van Hulst Jennifer A C,van Nimwegen Menno,van Uden Denise,Schuijs Martijn J,Pillai Saravanan Y,van Loo Geert,Hammad Hamida,Lambrecht Bart N,Hendriks Rudi W,Kool Mirjam The Journal of allergy and clinical immunology BACKGROUND:It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in T2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with T17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both T2 and T17 cell differentiation and is mediated through nuclear factor κB activation. Ablation of TNF-α-induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor κB activation in myeloid cells and DCs, was shown to control DC activation. OBJECTIVE:In this study we investigated the precise role of TNFAIP3 in myeloid cells for the development of T2- and T17-cell mediated asthma. METHODS:We exposed mice with conditional deletion of the Tnfaip3 gene in either myeloid cells (by using the lysozyme M [LysM] promotor) or specifically in DCs (by using the Cd11c promotor) to acute and chronic house dust mite (HDM)-driven asthma models. RESULTS:We demonstrated that reduced Tnfaip3 gene expression in DCs in either Tnfaip3 or Tnfaip3 mice dose-dependently controlled development of T17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely T2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific T17 cell differentiation through increased expression of the T17-instructing cytokines IL-1β, IL-6, and IL-23, whereas HDM-specific T2 cell differentiation was hampered by increased IL-12 and IL-6 production. CONCLUSIONS:These data show that the extent of TNFAIP3 expression in DCs controls T2/T17 cell differentiation. This implies that reducing DC activation could be a new pharmacologic intervention to treat patients with severe asthma who present with T17-mediated neutrophilic inflammation. 10.1016/j.jaci.2017.08.012
    IL-22 promotes allergic airway inflammation in epicutaneously sensitized mice. Leyva-Castillo Juan Manuel,Yoon Juhan,Geha Raif S The Journal of allergy and clinical immunology BACKGROUND:Serum IL-22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in T2-dominated skin inflammation that mimics atopic dermatitis and sensitizes the airways for antigen challenge-induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL-22. OBJECTIVE:We sought to determine the role of IL-22 in antigen-driven airway allergic inflammation after inhalation challenge in epicutaneously sensitized mice. METHODS:Wild-type (WT) and Il22 mice were sensitized epicutaneously or immunized intraperitoneally with ovalbumin (OVA) and challenged intranasally with antigen. OVA T-cell receptor-specific T cells were T22 polarized in vitro. Airway inflammation, mRNA levels in the lungs, and airway hyperresponsiveness (AHR) were examined. RESULTS:Epicutaneous sensitization preferentially elicited an IL-22 response compared with intraperitoneal immunization. Intranasal challenge of mice epicutaneously sensitized with OVA elicited in the lungs Il22 mRNA expression, IL-22 production, and accumulation of CD3CD4IL-22 T cells that coexpressed IL-17A and TNF-α. Epicutaneously sensitized Il22 mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR after intranasal OVA challenge. Production of IL-13, IL-17A, and TNF-α was normal, but IFN-γ production was increased in lung cells from airway-challenged and epicutaneously sensitized Il22 mice. Intranasal instillation of IFN-γ-neutralizing antibody partially reversed the defect in eosinophil recruitment. WT recipients of T22-polarized WT, but not IL-22-deficient, T-cell receptor OVA-specific T cells, which secrete both IL-17A and TNF-α, had neutrophil-dominated airway inflammation and AHR on intranasal OVA challenge. Intranasal instillation of IL-22 with TNF-α, but not IL-17A, elicited neutrophil-dominated airway inflammation and AHR in WT mice, suggesting that loss of IL-22 synergy with TNF-α contributed to defective recruitment of neutrophils into the airways of Il22 mice. TNF-α, but not IL-22, blockade at the time of antigen inhalation challenge inhibited airway inflammation in epicutaneously sensitized mice. CONCLUSION:Epicutaneous sensitization promotes generation of antigen-specific IL-22-producing T cells that promote airway inflammation and AHR after antigen challenge, suggesting that IL-22 plays an important role in the atopic march. 10.1016/j.jaci.2018.05.032
    Advances in asthma in 2017: Mechanisms, biologics, and genetics. Grayson Mitchell H,Feldman Scott,Prince Benjamin T,Patel Priya J,Matsui Elizabeth C,Apter Andrea J The Journal of allergy and clinical immunology This review summarizes some of the most significant advances in asthma research over the past year. We first focus on novel discoveries in the mechanism of asthma development and exacerbation. This is followed by a discussion of potential new biomarkers, including the use of radiographic markers of disease. Several new biologics have become available to the clinician in the past year, and we summarize these advances and how they can influence the clinical delivery of asthma care. After this, important findings in the genetics of asthma and heterogeneity in phenotypes of the disease are explored, as is the role the environment plays in shaping the development and exacerbation of asthma. Finally, we conclude with a discussion of advances in health literacy and how they will affect asthma care. 10.1016/j.jaci.2018.08.033
    Transcriptional and functional diversity of human macrophage repolarization. Gharib Sina A,McMahan Ryan S,Eddy William E,Long Matthew E,Parks William C,Aitken Moira L,Manicone Anne M The Journal of allergy and clinical immunology BACKGROUND:Macrophage plasticity allows cells to adopt different phenotypes, a property with important implications in disorders such as cystic fibrosis (CF) and asthma. OBJECTIVE:We sought to examine the transcriptional and functional significance of macrophage repolarization from an M1 to an M2 phenotype and assess the role of a common human genetic disorder (CF) and a prototypical allergic disease (asthma) in this transformation. METHODS:Monocyte-derived macrophages were collected from healthy subjects and patients with CF and polarized to an M2 state by using IL-4, IL-10, glucocorticoids, apoptotic PMNs, or azithromycin. We performed transcriptional profiling and pathway analysis for each stimulus. We assessed the ability of M2-repolarized macrophages to respond to LPS rechallenge and clear apoptotic neutrophils and used murine models to determine conserved functional responses to IL-4 and IL-10. We investigated whether M2 signatures were associated with alveolar macrophage phenotypes in asthmatic patients. RESULTS:We found that macrophages exhibit highly diverse responses to distinct M2-polarizing stimuli. Specifically, IL-10 activated proinflammatory pathways and abrogated LPS tolerance, allowing rapid restoration of LPS responsiveness. In contrast, IL-4 enhanced LPS tolerance, dampening proinflammatory responses after repeat LPS challenge. A common theme observed across all M2 stimuli was suppression of interferon-associated pathways. We found that CF macrophages had intact reparative and transcriptional responses, suggesting that macrophage contributions to CF-related lung disease are primarily shaped by their environment. Finally, we leveraged in vitro-derived signatures to show that allergen provocation induces distinct M2 state transcriptional patterns in alveolar macrophages. CONCLUSION:Our findings highlight the diversity of macrophage polarization, attribute functional consequences to different M2 stimuli, and provide a framework to phenotype macrophages in disease states. 10.1016/j.jaci.2018.10.046
    Mast cells within cellular networks. Stassen Michael,Hartmann Ann-Kathrin,Delgado Sharon Jiménez,Dehmel Susann,Braun Armin The Journal of allergy and clinical immunology Mast cells are highly versatile in terms of their mode of activation by a host of stimuli and their ability to flexibly release a plethora of biologically highly active mediators. Within the immune system, mast cells can best be designated as an active nexus interlinking innate and adaptive immunity. Here we try to draw an arc from initiation of acute inflammatory reactions to microbial pathogens to development of adaptive immunity and allergies. This multifaceted nature of mast cells is made possible by interaction with multiple cell types of immunologic and nonimmunologic origin. Examples for the former include neutrophils, eosinophils, T cells, and professional antigen-presenting cells. These interactions allow mast cells to orchestrate inflammatory innate reactions and complex adaptive immunity, including the pathogenesis of allergies. Important partners of nonimmunologic origin include cells of the sensory neuronal system. The intimate association between mast cells and sensory nerve fibers allows bidirectional communication, leading to neurogenic inflammation. Evidence is accumulating that this mast cell/nerve crosstalk is of pathophysiologic relevance in patients with allergic diseases, such as asthma. 10.1016/j.jaci.2019.01.031
    GM-CSF instigates a dendritic cell-T-cell inflammatory circuit that drives chronic asthma development. Nobs Samuel Philip,Pohlmeier Lea,Li Fengqi,Kayhan Merve,Becher Burkhard,Kopf Manfred The Journal of allergy and clinical immunology BACKGROUND:Steroid-resistant asthma is often characterized by high levels of neutrophils and mixed T2/T17 immune profiles. Indeed, neutrophils are key drivers of chronic lung inflammation in multiple respiratory diseases. Their numbers correlate strongly with disease severity, and their presence is often associated with exacerbation of chronic lung inflammation. OBJECTIVE:What factors drive development of neutrophil-mediated chronic lung disease remains largely unknown, and we sought to study the role of GM-CSF as a potential regulator in chronic asthma. METHODS:Different experimental animal models of chronic asthma were used in combination with alveolar macrophage-reconstitution of global GM-CSF receptor knockout mice as well as cell-type-specific knockout animals to elucidate the role of GM-CSF signaling in chronic airway inflammation. RESULTS:We identify GM-CSF signaling as a critical factor regulating pulmonary accumulation of neutrophils. We show that although being not required for intrinsically regulating neutrophil migration, GM-CSF controls lung dendritic cell function, which in turn promotes T-cell-dependent recruitment of neutrophils to the airways. We demonstrate that GM-CSF regulates lung dendritic cell antigen uptake, transport, and T2/T17 cell priming in an intrinsic fashion, which in turn drives pulmonary granulocyte recruitment and contributes to development of airway hyperresponsiveness in chronic disease. CONCLUSIONS:We identify GM-CSF as a potentially novel therapeutic target in chronic lung inflammation, describing a GM-CSF-dependent lung conventional dendritic cell-T-cell-neutrophil axis that drives chronic lung disease. 10.1016/j.jaci.2020.12.638
    Mast cell chymase affects the functional properties of primary human airway fibroblasts: Implications for asthma. Zhao Xinran O,Lampinen Maria,Rollman Ola,Sommerhoff Christian P,Paivandy Aida,Pejler Gunnar The Journal of allergy and clinical immunology BACKGROUND:Mast cells (MCs) have a profound impact on allergic asthma. Under such conditions, MCs undergo degranulation, resulting in the release of exceptionally large amounts of MC-restricted proteases. However, the role of these proteases in asthma is only partially understood. OBJECTIVES:We sought to test our hypothesis that MC proteases can influence the functionality of human lung fibroblasts (HLFs). METHODS:Primary HLFs were treated with MC chymase or tryptase, followed by assessment of parameters related to fibroblast function. RESULTS:HLFs underwent major morphologic changes in response to chymase, showing signs of cellular contraction, but were refractory to tryptase. However, no effects of chymase on HLF viability or proliferation were seen. Chymase, but not tryptase, had a major impact on the output of extracellular matrix-associated compounds from the HLFs, including degradation of fibronectin and collagen-1, and activation of pro-matrix metalloprotease 2. Further, chymase induced the release of various chemotactic factors from HLFs. In line with this, conditioned medium from chymase-treated HLFs showed chemotactic activity on neutrophils. Transcriptome analysis revealed that chymase induced a proinflammatory gene transcription profile in HLFs, whereas tryptase had minimal effects. CONCLUSIONS:Chymase, but not tryptase, has a major impact on the phenotype of primary airway fibroblasts by modifying their output of extracellular matrix components and by inducing a proinflammatory phenotype. 10.1016/j.jaci.2021.07.020
    Epigenetic regulation of immune function in asthma. The Journal of allergy and clinical immunology Asthma is a common complex respiratory disease characterized by chronic airway inflammation and partially reversible airflow obstruction resulting from genetic and environmental determinants. Because epigenetic marks influence gene expression and can be modified by both environmental exposures and genetic variation, they are increasingly recognized as relevant to the pathogenesis of asthma and may be a key link between environmental exposures and asthma susceptibility. Unlike changes to DNA sequence, epigenetic signatures are dynamic and reversible, creating an opportunity for not only therapeutic targets but may serve as biomarkers to follow disease course and identify molecular subtypes in heterogeneous diseases such as asthma. In this review, we will examine the relationship between asthma and 3 key epigenetic processes that modify gene expression: DNA methylation, modification of histone tails, and noncoding RNAs. In addition to presenting a comprehensive assessment of the existing epigenetic studies focusing on immune regulation in asthma, we will discuss future directions for epigenetic investigation in allergic airway disease. 10.1016/j.jaci.2022.06.002
    Microbiome-Immune Interactions in Allergy and Asthma. The journal of allergy and clinical immunology. In practice The human microbiota has been established as a key regulator of host health, in large part due to its constant interaction with, and impact on, host immunity. A range of environmental exposures, spanning from the prenatal period through adulthood are now known to impact the composition and molecular productivity of microbiomes across mucosal and dermal tissues with short- and long-term consequences for host immune function. Here we review the more recent findings in the field that provide insights into how microbial-immune interactions promote and sustain immune dysfunction associated with allergy and asthma. We consider both early life microbiome perturbation and the molecular underpinnings of immune dysfunction associated with subsequent allergy and asthma development in childhood, as well as microbiome features that relate to phenotypic attributes of allergy and asthma in older patients with established disease. 10.1016/j.jaip.2022.05.038
    Extracellular Traps: A Novel Therapeutic Target for Severe Asthma. Journal of asthma and allergy Asthma is a complicated disease defined by a combination of clinical symptoms and physiological characteristics. Typically, asthma is diagnosed by the presence of episodic cough, wheezing, or dyspnea triggered by variable environmental factors (allergens and respiratory infections), and reversible airflow obstruction. To date, the majority of asthmatic patients have been adequately controlled by anti-inflammatory/bronchodilating agents, but those with severe asthma (SA) have not been sufficiently controlled by high-dose inhaled corticosteroids-long-acting beta-agonists plus additional controllers including leukotriene modifiers. Accordingly, these uncontrolled patients provoke a special issue, because they consume high healthcare resources, requiring innovative precision medicine solutions. Recently, phenotyping based on biomarkers of airway inflammation has led to elucidating the pathophysiological mechanism of SA, where emerging evidence has highlighted the significance of eosinophil or neutrophil extracellular traps contributing to the development of SA. Here, we aimed to provide current findings about extracellular traps as a novel therapeutic target for asthma to address medical unmet needs. 10.2147/JAA.S366014
    Asthma exacerbation associated with glucosamine supplement: an association between airways disorders and inflammatory bowel diseases? Current medicinal chemistry 10.2174/0929867329666220620124804
    Substance P promotes the progression of bronchial asthma through activating the PI3K/AKT/NF-κB pathway mediated cellular inflammation and pyroptotic cell death in bronchial epithelial cells. Cell cycle (Georgetown, Tex.) NOD-like receptor family pyrin domain containing three (NLRP3) inflammasome-mediated pyroptotic cell death and inflammation contribute to the pathogenesis of bronchial asthma, and it is reported that Substance P (SP) plays important role in the process, however, the detailed molecular mechanisms by which SP participates in the aggravation of bronchial asthma have not been fully studied. Here, our clinical data showed that SP and its receptor Neurokinin-1 receptor (NK1R) were significantly elevated in the plasma and peripheral blood mononuclear cell (PBMC) collected from patients with bronchial asthma, and further pre-clinical experiments evidenced that SP suppressed cell viability, accelerated lactate dehydrogenase (LDH) release, and upregulated ASC, Caspase-1, NLRP3, IL-1β and IL-18 to promote pyroptotic cell death and cellular inflammation in the human bronchial epithelial cells and asthmatic mice models and . Interestingly, SP-induced pyroptotic cell death was reversed by NK1R inhibitor L732138. Then, we uncovered the underlying mechanisms, and found that SP activated the downstream PI3K/AKT/NF-κB signal pathway in a NK1R-dependent manner, and blockage of this pathway by both PI3K inhibitor (LY294002) and NF-κB inhibitor (MG132) reversed SP-induced pyroptotic cell death and recovered cell viability in bronchial epithelial cells. Collectively, we concluded that SP interacted with its receptor NK1R to activate the PI3K/AKT/NF-κB pathway, which further triggered NLRP3-mediated pyroptotic cell death in the bronchial epithelial cells, resulting in the aggravation of bronchial asthma. 10.1080/15384101.2022.2092166
    Role of thymic stromal lymphopoietin in allergy and beyond. Nature reviews. Immunology Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that acts on multiple cell lineages, including dendritic cells, T cells, B cells, neutrophils, mast cells, eosinophils and innate lymphoid cells, affecting their maturation, survival and recruitment. It is best known for its role in promoting type 2 immune responses such as in allergic diseases and, in 2021, a monoclonal antibody targeting TSLP was approved for the treatment of severe asthma. However, it is now clear that TSLP has many other important roles in a variety of settings. Indeed, several genetic variants for TSLP are linked to disease severity, and chromosomal alterations in TSLP are common in certain cancers, indicating important roles of TSLP in disease. In this Review, we discuss recent advances in TSLP biology, highlighting how it regulates the tissue environment not only in allergic disease but also in infectious diseases, inflammatory diseases and cancer. Encouragingly, therapies targeting the TSLP pathway are being actively pursued for several diseases. 10.1038/s41577-022-00735-y