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1.
Immunity ; 57(6): 1274-1288.e6, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38821053

RESUMO

Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.


Assuntos
Dinoprostona , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Pulmão , Mastócitos , Camundongos Knockout , Animais , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Mastócitos/imunologia , Mastócitos/metabolismo , Dinoprostona/metabolismo , Camundongos , Interleucina-33/metabolismo , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Asma/imunologia , Asma/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Camundongos Endogâmicos C57BL , Inflamação/imunologia , Feminino , Masculino , Transdução de Sinais , Pneumonia/imunologia , Pneumonia/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-38704098

RESUMO

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood. OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation. METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro. RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts. CONCLUSION: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab's therapeutic efficacy in AERD.

3.
Nat Immunol ; 25(5): 902-915, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38589618

RESUMO

Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (TH2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Treg cells and TFH cells. TH2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify TH2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.


Assuntos
Fator 1-alfa Nuclear de Hepatócito , Hipersensibilidade , Fator 1 de Ligação ao Facilitador Linfoide , Células-Tronco Multipotentes , Fator 1 de Transcrição de Linfócitos T , Células Th2 , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/genética , Células Th2/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Hipersensibilidade/imunologia , Células-Tronco Multipotentes/metabolismo , Células-Tronco Multipotentes/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Linfopoietina do Estroma do Timo , Animais , Células Cultivadas , Camundongos
4.
Sci Immunol ; 9(92): eabq4341, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38306414

RESUMO

The olfactory neuroepithelium serves as a sensory organ for odors and forms part of the nasal mucosal barrier. Olfactory sensory neurons are surrounded and supported by epithelial cells. Among them, microvillous cells (MVCs) are strategically positioned at the apical surface, but their specific functions are enigmatic, and their relationship to the other specialized epithelial cells is unclear. Here, we establish that the family of MVCs comprises tuft cells and ionocytes in both mice and humans. Integrating analysis of the respiratory and olfactory epithelia, we define the distinct receptor expression of TRPM5+ tuft-MVCs compared with Gɑ-gustducinhigh respiratory tuft cells and characterize a previously undescribed population of glandular DCLK1+ tuft cells. To establish how allergen sensing by tuft-MVCs might direct olfactory mucosal responses, we used an integrated single-cell transcriptional and protein analysis. Inhalation of Alternaria induced mucosal epithelial effector molecules including Chil4 and a distinct pathway leading to proliferation of the quiescent olfactory horizontal basal stem cell (HBC) pool, both triggered in the absence of olfactory apoptosis. Alternaria- and ATP-elicited HBC proliferation was dependent on TRPM5+ tuft-MVCs, identifying these specialized epithelial cells as regulators of olfactory stem cell responses. Together, our data provide high-resolution characterization of nasal tuft cell heterogeneity and identify a function of TRPM5+ tuft-MVCs in directing the olfactory mucosal response to allergens.


Assuntos
Mucosa Olfatória , Células em Tufo , Humanos , Camundongos , Animais , Mucosa Olfatória/metabolismo , Mucosa Nasal , Células Epiteliais/metabolismo , Proliferação de Células , Quinases Semelhantes a Duplacortina
5.
bioRxiv ; 2023 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-37904989

RESUMO

Background: The airway epithelium plays a central role in the pathogenesis of chronic respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), but the mechanisms by which airway epithelial cells (EpCs) maintain inflammation are poorly understood. Objective: We hypothesized that transcriptomic assessment of sorted airway EpCs across the spectrum of differentiation would allow us to define mechanisms by which EpCs perpetuate airway inflammation. Methods: Ethmoid sinus EpCs from adult patients with CRS were sorted into 3 subsets, bulk RNA sequenced, and analyzed for differentially expressed genes and pathways. Single cell RNA-seq (scRNA-seq) datasets from eosinophilic and non-eosinophilic CRSwNP and bulk RNA-seq of EpCs from mild/moderate and severe asthma were assessed. Immunofluorescent staining and ex vivo functional analysis of sinus EpCs were used to validate our findings. Results: Analysis within and across purified EpC subsets revealed an enrichment in glycolytic programming in CRSwNP vs CRSsNP. Correlation analysis identified mammalian target of rapamycin complex 1 (mTORC1) as a potential regulator of the glycolytic program and identified EpC expression of cytokines and wound healing genes as potential sequelae. mTORC1 activity was upregulated in CRSwNP, and ex vivo inhibition demonstrated that mTOR is critical for EpC generation of CXCL8, IL-33, and CXCL2. Across patient samples, the degree of glycolytic activity was associated with T2 inflammation in CRSwNP, and with both T2 and non-T2 inflammation in severe asthma. Conclusions: Together, these findings highlight a metabolic axis required to support epithelial generation of cytokines critical to both chronic T2 and non-T2 inflammation in CRSwNP and asthma.

6.
J Allergy Clin Immunol ; 152(3): 700-710.e3, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37068712

RESUMO

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. Overproduction of cysteinyl leukotrienes and underproduction of prostaglandin E2 (PGE2) are hallmarks of AERD. A mouse model predicted a key role for the thromboxane-prostanoid (TP) receptor in AERD. OBJECTIVE: Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD. METHODS: A total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production. RESULTS: Ifetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P = .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV1 value than did participants receiving placebo (-18.8% ± 3.6% with ifetroban vs -8.4% ± 2.1% with placebo [P = .017]). Four weeks of ifetroban significantly increased urinary leukotriene E4 levels and decreased nasal PGE2 levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E4 and prostaglandin D2 metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE2 by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis. CONCLUSION: Contrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE2 production when COX-2 function is low.


Assuntos
Asma Induzida por Aspirina , Sinusite , Animais , Camundongos , Humanos , Prostaglandinas , Tromboxanos/uso terapêutico , Leucotrieno E4 , Receptores de Tromboxanos/uso terapêutico , Asma Induzida por Aspirina/tratamento farmacológico , Asma Induzida por Aspirina/diagnóstico , Aspirina/efeitos adversos , Eicosanoides , Dinoprostona , Homeostase , Sinusite/induzido quimicamente
7.
J Allergy Clin Immunol ; 151(6): 1536-1549, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36804595

RESUMO

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown. OBJECTIVE: We sought to determine the role of T2 cytokines in regulating airway BCs. METHODS: Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration. RESULTS: Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63+KRT5+NGFR+ BCs. In the sinonasal mucosa, BCAMhi BCs expressing TSLP, IL33, CCL26, and the canonical BC transcription factor TP63 are increased in patients with CRSwNP. In cultured BCs, IL-4/IL-13 increases the expression of BCAM and TP63 through an insulin receptor substrate-dependent signaling pathway that is increased in CRSwNP. CONCLUSIONS: These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Humanos , Animais , Camundongos , Receptor de Insulina/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Inflamação/metabolismo , Sinusite/metabolismo , Células Epiteliais/metabolismo , Transdução de Sinais , Doença Crônica , Pólipos Nasais/metabolismo , Rinite/metabolismo
8.
J Allergy Clin Immunol Pract ; 11(2): 492-499.e2, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36356925

RESUMO

BACKGROUND: Mas-related G protein-couple receptor x2 (Mrgprx2) activation underlies many common non-IgE-mediated adverse drug reactions (ADRs), yet the features of patients with reactions to Mrgprx2-activating drugs are unknown. OBJECTIVE: To characterize the patient-specific comorbidities and laboratory characteristics associated with listed reactions to Mrgprx2-activating drugs, including fluoroquinolones, morphine, neuromuscular blockade agents, vancomycin, and leuprolide. METHODS: We used a retrospective, observational cohort study design using electronic health record data from adults with an Mrgprx2-activating drug exposure recorded within a hospital system clinical Biobank. Odds ratios (ORs) and incidence rate ratios for clinical characteristics associated with ADRs, including immediate hypersensitivity reactions, were calculated using multivariable logistic regression. RESULTS: Among 59,763 patients exposed to Mrgprx2-activating drugs, 4846 had a listed ADR. Female sex, White race, asthma (OR: 1.81, 95% confidence interval [CI]: 1.68-1.94), chronic urticaria (OR: 1.73, 95% CI: 1.46-2.05), and mastocytosis (OR: 12.79, 95% CI: 5.98-27.02) were associated with increased odds of a reaction. Overall, patients with allergic disease had 1.21 times the rate of an ADR compared with patients without allergic disease. Elevated absolute eosinophil count was inversely associated with reactions, and there was no association with elevated total IgE. Observed associations were similar in a patient subgroup with immediate-type hypersensitivity reactions. CONCLUSION: Specific allergic diseases and common allergic biomarkers are differentially associated with ADRs to Mrgprx2-activating drugs. These findings from a large, "real world" drug-exposed population highlight clinical factors that may contribute to non-IgE-mediated drug allergy.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hipersensibilidade Imediata , Hipersensibilidade , Humanos , Feminino , Registros Eletrônicos de Saúde , Bancos de Espécimes Biológicos , Estudos Retrospectivos , Mastócitos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Proteínas de Ligação ao GTP , Degranulação Celular , Proteínas do Tecido Nervoso/metabolismo , Receptores de Neuropeptídeos/metabolismo
9.
J Allergy Clin Immunol ; 151(2): 301-309, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36184313

RESUMO

Aspirin-exacerbated respiratory disease has fascinated and frustrated specialists in allergy/immunology, pulmonology, and otorhinolaryngology for decades. It generally develops in previously healthy young adults and is unremitting and challenging to treat. The classical triad of asthma, nasal polyposis, and pathognomonic respiratory reactions to aspirin and other cyclooxygenase-1 inhibitors is accompanied by high levels of mast cell activation, cysteinyl leukotriene production, platelet activation, and severe type 2 respiratory inflammation. The "unbraking" of mast cell activation and further cysteinyl leukotriene generation induced by cyclooxygenase-1 inhibition reflect an idiosyncratic dependency on cyclooxygenase-1-derived products, likely prostaglandin E2, to maintain a tenuous homeostasis. Although cysteinyl leukotrienes are clear disease effectors, little else was known about their cellular sources and targets, and the contributions from other mediators and type 2 respiratory inflammation effector cells to disease pathophysiology were unknown until recently. The applications of targeted biological therapies, single-cell genomics, and transgenic animal approaches have substantially advanced our understanding of aspirin-exacerbated respiratory disease pathogenesis and treatment and have also revealed disease heterogeneity. This review covers novel insights into the immunopathogenesis of aspirin-exacerbated respiratory disease from each of these lines of research, including the roles of lipid mediators, effector cell populations, and inflammatory cytokines, discusses unanswered questions regarding cause and pathogenesis, and considers potential future therapeutic options.


Assuntos
Asma Induzida por Aspirina , Animais , Ciclo-Oxigenase 1 , Aspirina/efeitos adversos , Leucotrienos , Inflamação
10.
Trans Am Clin Climatol Assoc ; 132: 92-103, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36196164

RESUMO

Type 2 inflammation (T2I) underlies the pathogenesis of asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis. Mast cells (MCs) are tissue resident hematopoietic effector cells thought to play major roles in T2I. Two subtypes of human MCs are recognized based on immunohistochemical differences. MCs expressing tryptase but not chymase (MCT) reside within mucosal epithelial surfaces, and MCs expressing tryptase, chymase, and cathepsin G (MCTC) reside in submucosal, perivascular and intraneural locations. During T2I, MCs (particularly MCT) increase markedly by unclear mechanisms. Single cell genomic studies reveal that traditional histochemical categorization vastly underestimates the extent of MC functional heterogeneity. MCT and MCTC likely reflect endpoints of a developmental continuum, emerging from a transitional stage of development in which MCs expand through in situ proliferation. This mechanism, likely driven by interleukin 4 and other cytokines, is unique among granulocytes and carries substantial implications for pathogenesis and therapy of T2I-associated diseases.


Assuntos
Interleucina-4 , Mastócitos , Catepsina G/metabolismo , Humanos , Inflamação , Interleucina-4/metabolismo , Triptases/metabolismo
11.
J Allergy Clin Immunol ; 150(4): 739-747, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36205448

RESUMO

Mast cells (MCs) are widely recognized as central effector cells during type 2 inflammatory reactions and thought to also play a role in innate immune responses, wound healing, and potentially cancer. Circulating progenitor cells mature to MCs in peripheral tissues, where they exhibit phenotypic and functional heterogeneity. This diversity likely originates from differences in MC development imprinted by microenvironmental signals. The advent of single-cell transcriptomics reveals MC diversity beyond differences in proteases that were classically used to identify MC phenotypes. Here, we provide an overview of the current knowledge on MC progenitor differentiation and characteristics, and MC heterogeneity seen in health versus disease, that are drastically advanced through single-cell profiling technologies. This powerful approach can provide detailed cellular maps of tissues to decipher the complex cellular functions and interactions that may lead to identifying candidate factors to target in therapies.


Assuntos
Hipersensibilidade , Transcriptoma , Diferenciação Celular , Humanos , Hipersensibilidade/metabolismo , Mastócitos/metabolismo , Peptídeo Hidrolases/metabolismo , Células-Tronco
12.
J Immunol ; 209(12): 2293-2303, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36307120

RESUMO

Innate immune responses to innocuous Ags can either prevent or facilitate adaptive type 2 allergic inflammation, but the mechanisms are incompletely understood. We now demonstrate that macrophage UDP-specific type 6 purinergic (P2Y6) receptors selectively activate NFATC2, a member of the NFAT family, to drive an innate IL-12/IFN-γ axis that prevents type 2 allergic inflammation. UDP priming potentiated IL-12p40 production in bone marrow-derived macrophages (BMMs) stimulated by the house dust mite Dermatophagoides farinae (Df) in a P2Y6-dependent manner. Inhibitions of phospholipase C, calcium increase, and calcineurin eliminated UDP-potentiated Df-induced IL-12p40 production. UDP specifically induced nuclear translocation of NFATC2, but not NFATC1 and NFATC3, in BMMs in a P2Y6-dependent manner. UDP-potentiated IL-12p40 production by BMMs and Df-induced IL-12p40 gene expression by alveolar macrophages were abrogated in cells from Nfatc2 knockout mice. Pulmonary transplantation of wild-type but not Nfatc2 knockout macrophages increased Df-induced IL-12 production and IFN-γ expression in P2ry6 fl/fl/Cre/+ recipient mice. Finally, Nfatc2 knockout mice showed significantly increased indices of type 2 immunopathology in response to Df challenge, similar to P2ry6 fl/fl/Cre/+ mice. Thus, macrophage P2Y6 receptor signaling selectively utilizes NFATC2 to potentiate an innate IL-12/IFN-γ axis, a potential mechanism that protects against inappropriate type 2 immune responses.


Assuntos
Alveolite Alérgica Extrínseca , Fatores de Transcrição NFATC , Receptores Purinérgicos P2 , Animais , Camundongos , Alveolite Alérgica Extrínseca/metabolismo , Inflamação/metabolismo , Subunidade p40 da Interleucina-12/metabolismo , Macrófagos , Camundongos Knockout , Difosfato de Uridina/metabolismo , Receptores Purinérgicos P2/metabolismo , Fatores de Transcrição NFATC/metabolismo
13.
Eur J Pharmacol ; 934: 175257, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36116518

RESUMO

BACKGROUND: Cysteinyl-maresins, also known as maresin-conjugates in tissue regeneration (MCTRs), are recently discovered lipid mediators proposed to reduce airway inflammation. OBJECTIVE: To investigate the influence of MCTRs on IL-13-induced airway hyperresponsiveness in isolated human and mice airways. METHODS: Before responsiveness to contractile agonists were assessed in myographs, human small bronchi were cultured for 2 days and mouse tracheas were cultured for 1-4 days. During the culture procedure airways were exposed to interleukin (IL)-13 in the presence or absence of MCTRs. Signalling mechanisms were explored using pharmacologic agonists and antagonists, and genetically modified mice. RESULTS: IL-13 treatment increased contractions to histamine, carbachol and leukotriene D4 (LTD4) in human small bronchi, and to 5-hydroxytryptamine (5-HT) in mouse trachea. In both preparations, co-incubation of the explanted tissues with MCTR3 reduced the IL-13 induced enhancement of contractions. In mouse trachea, this inhibitory effect of MCTR3 was blocked by three different CysLT1 receptor antagonists (montelukast, zafirlukast and pobilukast) during IL-13 exposure. Likewise, MCTR3 failed to reduce the IL-13-induced 5-HT responsiveness in mice deficient of the CysLT1 receptor. However, co-incubation with the classical CysLT1 receptor agonist LTD4 did not alter the IL-13-induced 5-HT hyperreactivity. CONCLUSIONS: MCTR3, but not LTD4, decreased the IL-13-induced airway hyperresponsiveness by activation of the CysLT1 receptor. The distinct actions of the two lipid mediators on the CysLT1 receptor suggest an alternative signalling pathway appearing under inflammatory conditions, where this new action of MCTR3 implicates potential to inhibit airway hyperresponsiveness in asthma.


Assuntos
Interleucina-13 , Leucotrieno D4 , Humanos , Camundongos , Animais , Leucotrieno D4/farmacologia , Leucotrieno D4/fisiologia , Interleucina-13/farmacologia , Serotonina , Carbacol/farmacologia , Histamina , Receptores de Leucotrienos/metabolismo , Antagonistas de Leucotrienos
14.
J Allergy Clin Immunol ; 149(6): 1919-1925, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35427642

RESUMO

Mast cells (MCs) contribute prominently to all allergic diseases, yet are still poorly understood owing to their exclusive residence in tissues. Recently, the use of RNA-sequencing, proteomics, and other technological advances have accelerated the acquisition of new knowledge. This includes an expanded definition of MC heterogeneity and developmental origins, previously unrecognized functions for MCs, discoveries of genetic causes of MC-related disorders, the introduction of new therapies for clonal MC disease, and the identification of new potential target for treatments. This issue of Advances addresses key studies from 2020 to 2021.


Assuntos
Hipersensibilidade , Mastocitose , Células Cultivadas , Humanos , Hipersensibilidade/genética , Mastócitos , Mastocitose/genética , Mastocitose/terapia
15.
J Clin Invest ; 132(1)2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34981786

RESUMO

IL-4- and IL-13-driven epithelial cell expression of 15 lipoxygenase 1 (15LO1) is a consistent feature of eosinophil-dominated asthma known as type 2-high (T2-high) asthma. The abundant soluble products of arachidonic acid (AA) metabolized by 15LO1 reflect a high level of enzymatic activity in asthma and chronic rhinosinusitis. However, the precise role of 15LO1 and its products in disease pathogenesis remains enigmatic. In this issue of the JCI, Nagasaki and colleagues demonstrate a role for 15LO1 in controlling redox balance and epithelial homeostasis in T2-high asthma by metabolizing AA that is esterified to membrane phospholipids. The findings may pave the way toward the development of 15LO1 inhibitors as asthma treatments.


Assuntos
Araquidonato 15-Lipoxigenase , Asma , Araquidonato 15-Lipoxigenase/genética , Ácido Araquidônico , Asma/tratamento farmacológico , Células Epiteliais , Humanos , Lipoxigenase
16.
Sci Immunol ; 6(66): eabj0474, 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34932383

RESUMO

Aeroallergen sensing by airway epithelial cells triggers pathogenic immune responses leading to type 2 inflammation, the hallmark of chronic airway diseases such as asthma. Tuft cells are rare epithelial cells and the dominant source of interleukin-25 (IL-25), an epithelial cytokine, and cysteinyl leukotrienes (CysLTs), lipid mediators of vascular permeability and chemotaxis. How these two mediators derived from the same cell might cooperatively promote type 2 inflammation in the airways has not been clarified. Here, we showed that inhalation of the parent leukotriene C4 (LTC4) in combination with a subthreshold dose of IL-25 led to activation of two innate immune cells: inflammatory type 2 innate lymphoid cell (ILC2) for proliferation and cytokine production, and dendritic cells (DCs). This cooperative effect led to a much greater recruitment of eosinophils and CD4+ T cell expansion indicative of synergy. Whereas lung eosinophilia was dominantly mediated through the classical CysLT receptor CysLT1R, type 2 cytokines and activation of innate immune cells required signaling through CysLT1R and partially CysLT2R. Tuft cell­specific deletion of Ltc4s, the terminal enzyme required for CysLT production, reduced lung inflammation and the systemic immune response after inhalation of the mold aeroallergen Alternaria; this effect was further enhanced by concomitant blockade of IL-25. Our findings identified a potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuft cells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs.


Assuntos
Cisteína/imunologia , Células Epiteliais/imunologia , Interleucinas/imunologia , Leucotrienos/imunologia , Pneumonia/imunologia , Animais , Camundongos , Camundongos Transgênicos
17.
Sci Immunol ; 6(56)2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637594

RESUMO

Mast cells (MCs) play a pathobiologic role in type 2 (T2) allergic inflammatory diseases of the airway, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Distinct MC subsets infiltrate the airway mucosa in T2 disease, including subepithelial MCs expressing the proteases tryptase and chymase (MCTC) and epithelial MCs expressing tryptase without chymase (MCT). However, mechanisms underlying MC expansion and the transcriptional programs underlying their heterogeneity are poorly understood. Here, we use flow cytometry and single-cell RNA-sequencing (scRNA-seq) to conduct a comprehensive analysis of human MC hyperplasia in CRSwNP, a T2 cytokine-mediated inflammatory disease. We link discrete cell surface phenotypes to the distinct transcriptomes of CRSwNP MCT and MCTC, which represent polarized ends of a transcriptional gradient of nasal polyp MCs. We find a subepithelial population of CD38highCD117high MCs that is markedly expanded during T2 inflammation. These CD38highCD117high MCs exhibit an intermediate phenotype relative to the expanded MCT and MCTC subsets. CD38highCD117high MCs are distinct from circulating MC progenitors and are enriched for proliferation, which is markedly increased in CRSwNP patients with aspirin-exacerbated respiratory disease, a severe disease subset characterized by increased MC burden and elevated MC activation. We observe that MCs expressing a polyp MCT-like effector program are also found within the lung during fibrotic diseases and asthma, and further identify marked differences between MCTC in nasal polyps and skin. These results indicate that MCs display distinct inflammation-associated effector programs and suggest that in situ MC proliferation is a major component of MC hyperplasia in human T2 inflammation.


Assuntos
Mucosa Nasal/patologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , Idoso , Proliferação de Células , Endoscopia , Feminino , Citometria de Fluxo , Humanos , Masculino , Mastócitos , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/imunologia , Mucosa Nasal/cirurgia , Pólipos Nasais/patologia , Procedimentos Cirúrgicos Nasais , RNA-Seq , Rinite/patologia , Rinite/cirurgia , Análise de Célula Única , Sinusite/patologia , Sinusite/cirurgia , Adulto Jovem
18.
J Exp Med ; 218(1)2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-32946563

RESUMO

Murine mast cells (MCs) contain two lineages: inducible bone marrow-derived mucosal MCs (MMCs) and constitutive embryonic-derived connective tissue MCs (CTMCs). Here, we use RNA sequencing, flow cytometry, and genetic deletion in two allergic lung inflammation models to define these two lineages. We found that inducible MCs, marked by ß7 integrin expression, are highly distinct from airway CTMCs at rest and during inflammation and unaffected by targeted CTMC deletion. ß7High MCs expand and mature during lung inflammation as part of a TGF-ß-inducible transcriptional program that includes the MMC-associated proteases Mcpt1 and Mcpt2, the basophil-associated protease Mcpt8, granule components, and the epithelial-binding αE integrin. In vitro studies using bone marrow-derived MCs (BMMCs) identified a requirement for SCF in this this TGF-ß-mediated development and found that epithelial cells directly elicit TGF-ß-dependent BMMC up-regulation of mMCP-1 and αE integrin. Thus, our findings characterize the expansion of a distinct inducible MC subset in C57BL/6 mice and highlight the potential for epithelium to direct MMC development.


Assuntos
Asma/imunologia , Células da Medula Óssea/imunologia , Linhagem da Célula/imunologia , Mastócitos/imunologia , Mucosa Respiratória/imunologia , Animais , Asma/embriologia , Asma/genética , Asma/patologia , Células da Medula Óssea/patologia , Linhagem da Célula/genética , Cadeias beta de Integrinas/genética , Cadeias beta de Integrinas/imunologia , Mastócitos/patologia , Camundongos , Camundongos Transgênicos , Mucosa Respiratória/embriologia , Mucosa Respiratória/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Triptases/genética , Triptases/imunologia
19.
J Allergy Clin Immunol ; 148(1): 195-208.e5, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33285161

RESUMO

BACKGROUND: The 3 cysteinyl leukotrienes (cysLTs), leukotriene (LT) C4 (LTC4), LTD4, and LTE4, have different biologic half-lives, cellular targets, and receptor specificities. CysLT2R binds LTC4 and LTD4in vitro with similar affinities, but it displays a marked selectivity for LTC4in vivo. LTC4, but not LTD4, strongly potentiates allergen-induced pulmonary eosinophilia in mice through a CysLT2R-mediated, platelet- and IL-33-dependent pathway. OBJECTIVE: We sought to determine whether LTD4 functionally antagonizes LTC4 signaling at CysLT2R. METHODS: We used 2 different in vivo models of CysLT2R-dependent immunopathology, as well as ex vivo activation of mouse and human platelets. RESULTS: LTC4-induced CD62P expression; HMGB1 release; and secretions of thromboxane A2, CXCL7, and IL-33 by mouse platelets were all were blocked by a selective CysLT2R antagonist and inhibited by LTD4. These effects did not depend on CysLT1R. Inhaled LTD4 blocked LTC4-mediated potentiation of ovalbumin-induced eosinophilic inflammation; recruitment of platelet-adherent eosinophils; and increases in IL-33, IL-4, IL-5, and IL-13 levels in lung tissue. In contrast, the effect of administration of LTE4, the preferred ligand for CysLT3R, was additive with LTC4. The administration of LTD4 to Ptges-/- mice, which display enhanced LTC4 synthesis similar to that in aspirin-exacerbated respiratory disease, completely blocked the physiologic response to subsequent lysine-aspirin inhalation challenges, as well as increases in levels of IL-33, type 2 cytokines, and biochemical markers of mast cell and platelet activation. CONCLUSION: The conversion of LTC4 to LTD4 may limit the duration and extent of potentially deleterious signaling through CysLT2R, and it may contribute to the therapeutic properties of desensitization to aspirin in aspirin-exacerbated respiratory disease.


Assuntos
Plaquetas/imunologia , Leucotrieno C4/imunologia , Leucotrieno D4/imunologia , Pulmão/imunologia , Ativação Plaquetária/imunologia , Animais , Asma/imunologia , Cisteína/imunologia , Citocinas/imunologia , Leucotrieno E4/imunologia , Leucotrienos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Eosinofilia Pulmonar/imunologia , Receptores de Leucotrienos/imunologia
20.
J Allergy Clin Immunol ; 145(6): 1574-1584, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32199912

RESUMO

BACKGROUND: The cause of severe nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but upstream drivers of local antibody production in nasal polyps are undetermined. OBJECTIVE: We sought to identify upstream drivers and phenotypic properties of local antibody-expressing cells in nasal polyps from subjects with AERD. METHODS: Sinus tissue was obtained from subjects with AERD, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps, and controls without CRS. Tissue antibody levels were quantified via ELISA and immunohistochemistry and were correlated with disease severity. Antibody-expressing cells were profiled with single-cell RNA sequencing, flow cytometry, and immunofluorescence, with IL-5Rα function determined through IL-5 stimulation and subsequent RNA sequencing and quantitative PCR. RESULTS: Tissue IgE and IgG4 levels were elevated in AERD compared with in controls (P < .01 for IgE and P < .001 for IgG4 vs CRSwNP). Subjects with AERD whose nasal polyps recurred rapidly had higher IgE levels than did subjects with AERD, with slower regrowth (P = .005). Single-cell RNA sequencing revealed increased IL5RA, IGHG4, and IGHE in antibody-expressing cells from patients with AERD compared with antibody-expressing cells from patients with CRSwNP. There were more IL-5Rα+ plasma cells in the polyp tissue from those with AERD than in polyp tissue from those with CRSwNP (P = .026). IL-5 stimulation of plasma cells in vitro induced changes in a distinct set of transcripts. CONCLUSIONS: Our study identifies an increase in antibody-expressing cells in AERD defined by transcript enrichment of IL5RA and IGHG4 or IGHE, with confirmed surface expression of IL-5Rα and functional IL-5 signaling. Tissue IgE and IgG4 levels are elevated in AERD, and higher IgE levels are associated with faster nasal polyp regrowth. Our findings suggest a role for IL-5Rα+ antibody-expressing cells in facilitating local antibody production and severe nasal polyps in AERD.


Assuntos
Aspirina/efeitos adversos , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Subunidade alfa de Receptor de Interleucina-5/metabolismo , Pólipos Nasais/metabolismo , Sinusite/metabolismo , Adulto , Idoso , Anticorpos/metabolismo , Feminino , Humanos , Interleucina-5/metabolismo , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/induzido quimicamente , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Análise de Sequência de RNA/métodos , Sinusite/induzido quimicamente , Adulto Jovem
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