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1.
Am J Respir Crit Care Med ; 207(11): 1486-1497, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36952660

RESUMO

Rationale: Type 2 inflammation has been described in people with cystic fibrosis (CF). Whether loss of CFTR (cystic fibrosis transmembrane conductance regulator) function contributes directly to a type 2 inflammatory response has not been fully defined. Objectives: The potent alarmin IL-33 has emerged as a critical regulator of type 2 inflammation. We tested the hypothesis that CFTR deficiency increases IL-33 expression and/or release and deletion of IL-33 reduces allergen-induced inflammation in the CF lung. Methods: Human airway epithelial cells (AECs) grown from non-CF and CF cell lines and Cftr+/+ and Cftr-/- mice were used in this study. Pulmonary inflammation in Cftr+/+ and Cftr-/- mice with and without IL-33 or ST2 (IL-1 receptor-like 1) germline deletion was determined by histological analysis, BAL, and cytokine analysis. Measurements and Main Results: After allergen challenge, both CF human AECs and Cftr-/- mice had increased IL-33 expression compared with control AECs and Cftr+/+ mice, respectively. DUOX1 (dual oxidase 1) expression was increased in CF human AECs and Cftr-/- mouse lungs compared with control AECs and lungs from Cftr+/+ mice and was necessary for the increased IL-33 release in Cftr-/- mice compared with Cftr+/+ mice. IL-33 stimulation of Cftr-/- CD4+ T cells resulted in increased type 2 cytokine production compared with Cftr+/+ CD4+ T cells. Deletion of IL-33 or ST2 decreased both type 2 inflammation and neutrophil recruitment in Cftr-/- mice compared with Cftr+/+ mice. Conclusions: Absence of CFTR reprograms airway epithelial IL-33 release and licenses IL-33-dependent inflammation. Modulation of the IL-33/ST2 axis represents a novel therapeutic target in CF type 2-high and neutrophilic inflammation.


Assuntos
Fibrose Cística , Camundongos , Animais , Humanos , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Interleucina-33/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Inflamação/metabolismo , Citocinas/metabolismo , Alérgenos , Células Epiteliais/metabolismo
2.
J Immunol ; 205(4): 1157-1166, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32690653

RESUMO

The cyclooxygenase (COX) metabolic pathway regulates immune responses and inflammation. The effect of the COX pathway on innate pulmonary inflammation induced by protease-containing fungal allergens, such as Alternaria alternata, is not fully defined. In this study, we tested the hypothesis that COX inhibition augments Alternaria-induced pulmonary group 2 innate lymphoid cell (ILC2) responses and IL-33 release. Mice were treated with the COX inhibitors indomethacin, flurbiprofen, or vehicle and challenged intranasally with Alternaria extract for four consecutive days to induce innate lung inflammation. We found that indomethacin and flurbiprofen significantly increased the numbers of ILC2 and IL-5 and IL-13 expression by ILC2 in the lung. Indomethacin also increased ILC2 proliferation, the percentages of eosinophils, and mucus production in the lung. Both indomethacin and flurbiprofen augmented the release of IL-33 in bronchoalveolar lavage fluid after Alternaria challenge, suggesting that more IL-33 was available for ILC2 activation and that a COX product(s) inhibited IL-33 release. This is supported by the in vitro finding that the COX product PGE2 and the PGI2 analogs cicaprost decreased Alternaria extract-induced IL-33 release by human bronchial epithelial cells. Although contrasting effects of PGD2, PGE2, and PGI2 on ILC2 responses have been previously reported, the overall effect of the COX pathway on ILC2 function is inhibitory in Alternaria-induced innate airway inflammation.


Assuntos
Alternaria/imunologia , Inibidores de Ciclo-Oxigenase/farmacologia , Imunidade Inata/efeitos dos fármacos , Interleucina-33/imunologia , Linfócitos/efeitos dos fármacos , Alérgenos/imunologia , Alternariose/imunologia , Alternariose/metabolismo , Alternariose/microbiologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Proliferação de Células/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/microbiologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Feminino , Flurbiprofeno/imunologia , Humanos , Imunidade Inata/imunologia , Indometacina/farmacologia , Interleucina-13/imunologia , Interleucina-5/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Linfócitos/imunologia , Linfócitos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Pneumonia/metabolismo , Pneumonia/microbiologia
3.
Gastroenterology ; 159(6): 2077-2091.e8, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32891625

RESUMO

BACKGROUND & AIMS: Severe injury to the lining of the stomach leads to changes in the epithelium (reprogramming) that protect and promote repair of the tissue, including development of spasmolytic polypeptide-expressing metaplasia (SPEM) and tuft and foveolar cell hyperplasia. Acute gastric damage elicits a type-2 inflammatory response that includes production of type-2 cytokines and infiltration by eosinophils and alternatively activated macrophages. Stomachs of mice that lack interleukin 33 (IL33) or interleukin 13 (IL13) did not undergo epithelial reprogramming after drug-induced injury. We investigated the role of group 2 innate lymphoid cells (ILC2s) in gastric epithelial repair. METHODS: Acute gastric injury was induced in C57BL/6J mice (wild-type and RAG1 knockout) by administration of L635. We isolated ILC2s by flow cytometry from stomachs of mice that were and were not given L635 and performed single-cell RNA sequencing. ILC2s were depleted from wild-type and RAG1-knockout mice by administration of anti-CD90.2. We assessed gastric cell lineages, markers of metaplasia, inflammation, and proliferation. Gastric tissue microarrays from patients with gastric adenocarcinoma were analyzed by immunostaining. RESULTS: There was a significant increase in the number of GATA3-positive ILC2s in stomach tissues from wild-type mice after L635-induced damage, but not in stomach tissues from IL33-knockout mice. We characterized a marker signature of gastric mucosal ILC2s and identified a transcription profile of metaplasia-associated ILC2s, which included changes in expression of Il5, Il13, Csf2, Pd1, and Ramp3; these changes were validated by quantitative polymerase chain reaction and immunocytochemistry. Depletion of ILC2s from mice blocked development of metaplasia after L635-induced injury in wild-type and RAG1-knockout mice and prevented foveolar and tuft cell hyperplasia and infiltration or activation of macrophages after injury. Numbers of ILC2s were increased in stomach tissues from patients with SPEM compared with patients with normal corpus mucosa. CONCLUSIONS: In analyses of stomach tissues from mice with gastric tissue damage and patients with SPEM, we found evidence of type 2 inflammation and increased numbers of ILC2s. Our results suggest that ILC2s coordinate the metaplastic response to severe gastric injury.


Assuntos
Mucosa Gástrica/patologia , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Animais , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/imunologia , Humanos , Interleucina-33/genética , Metaplasia/induzido quimicamente , Metaplasia/genética , Metaplasia/imunologia , Camundongos , Camundongos Knockout
6.
Circ Res ; 118(8): 1233-43, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26988069

RESUMO

RATIONALE: Accumulating evidence supports a role of adaptive immunity and particularly T cells in the pathogenesis of hypertension. Formation of memory T cells, which requires the costimulatory molecule CD70 on antigen-presenting cells, is a cardinal feature of adaptive immunity. OBJECTIVE: To test the hypothesis that CD70 and immunologic memory contribute to the blood pressure elevation and renal dysfunction mediated by repeated hypertensive challenges. METHODS AND RESULTS: We imposed repeated hypertensive challenges using either N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME)/high salt or repeated angiotensin II stimulation in mice. During these challenges effector memory T cells (T(EM)) accumulated in the kidney and bone marrow. In the L-NAME/high-salt model, memory T cells of the kidney were predominant sources of interferon-γ and interleukin-17A, known to contribute to hypertension. L-NAME/high salt increased macrophage and dendritic cell surface expression of CD70 by 3- to 5-fold. Mice lacking CD70 did not accumulate T(EM) cells and did not develop hypertension to either high salt or the second angiotensin II challenge and were protected against renal damage. Bone marrow-residing T(EM) cells proliferated and redistributed to the kidney in response to repeated salt feeding. Adoptively transferred T(EM) cells from hypertensive mice homed to the bone marrow and spleen and expanded on salt feeding of the recipient mice. CONCLUSIONS: Our findings illustrate a previously undefined role of CD70 and long-lived T(EM) cells in the development of blood pressure elevation and end-organ damage that occur on delayed exposure to mild hypertensive stimuli. Interventions to prevent repeated hypertensive surges could attenuate formation of hypertension-specific T(EM) cells.


Assuntos
Pressão Sanguínea/fisiologia , Ligante CD27/deficiência , Hipertensão/metabolismo , Nefropatias/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Mediadores da Inflamação/metabolismo , Nefropatias/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NG-Nitroarginina Metil Éster/toxicidade , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
7.
Am J Physiol Renal Physiol ; 313(2): F141-F144, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28404590

RESUMO

Hypertension is growing in epidemic proportions worldwide and is now the leading preventable cause of premature death. For over a century, we have known that the kidney plays a critical role in blood pressure regulation. Specifically, abnormalities in renal sodium transport appear to be a final common pathway that gives rise to elevated blood pressure regardless of the nature of the initial hypertensive stimulus. However, it is only in the past decade that we have come to realize that inflammatory cytokines secreted by innate and adaptive immune cells, as well as renal epithelial cells, can modulate the expression and activity of sodium transporters all along the nephron, leading to alterations in pressure natriuresis, sodium and water balance, and ultimately hypertension. This mini-review highlights specific cytokines and the transporters that they regulate and discusses why inflammatory cytokines may have evolved to serve this function.


Assuntos
Pressão Sanguínea , Citocinas/metabolismo , Células Epiteliais/metabolismo , Canais Epiteliais de Sódio/metabolismo , Hipertensão/metabolismo , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Citocinas/imunologia , Células Epiteliais/imunologia , Canais Epiteliais de Sódio/imunologia , Humanos , Hipertensão/imunologia , Hipertensão/fisiopatologia , Mediadores da Inflamação/imunologia , Rim/imunologia , Rim/fisiopatologia , Proteínas de Membrana Transportadoras/imunologia , Reabsorção Renal , Transdução de Sinais
8.
Mol Syst Biol ; 11(1): 799, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25882670

RESUMO

Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3(-/-) mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3(-/-) mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Angiotensina II/metabolismo , Animais , Índice de Massa Corporal , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Redes Reguladoras de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Lineares , Masculino , Proteínas de Membrana , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Domínios e Motivos de Interação entre Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Biologia de Sistemas , Transcriptoma , Adulto Jovem
9.
Cell Mol Gastroenterol Hepatol ; 18(3): 101366, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38815928

RESUMO

BACKGROUND & AIMS: Type 2 innate lymphoid cells (ILC2s) and interleukin-13 (IL-13) promote the onset of spasmolytic polypeptide-expressing metaplasia (SPEM) cells. However, little is known about molecular effects of IL-13 in SPEM cells. We now sought to establish a reliable organoid model, Meta1 gastroids, to model SPEM cells in vitro. We evaluated cellular and molecular effects of ILC2s and IL-13 on maturation and proliferation of SPEM cells. METHODS: We performed single-cell RNA sequencing to characterize Meta1 gastroids, which were derived from stomachs of Mist1-Kras transgenic mice that displayed pyloric metaplasia. Cell sorting was used to isolate activated ILC2s from stomachs of IL-13-tdTomato reporter mice treated with L635. Three-dimensional co-culture was used to determine the effects of ILC2s on Meta1 gastroids. Mouse normal or metaplastic (Meta1) and human metaplastic gastroids were cultured with IL-13 to evaluate cell responses. Air-Liquid Interface culture was performed to test long-term culture effects of IL-13. In silico analysis determined possible STAT6-binding sites in gene promoter regions. STAT6 inhibition was performed to corroborate STAT6 role in SPEM cells maturation. RESULTS: Meta1 gastroids showed the characteristics of SPEM cell lineages in vitro even after several passages. We demonstrated that co-culture with ILC2s or IL-13 treatment can induce phosphorylation of STAT6 in Meta1 and normal gastroids and promote the maturation and proliferation of SPEM cell lineages. IL-13 up-regulated expression of mucin-related proteins in human metaplastic gastroids. Inhibition of STAT6 blocked SPEM-related gene expression in Meta1 gastroids and maturation of SPEM in both normal and Meta1 gastroids. CONCLUSIONS: IL-13 promotes the maturation and proliferation of SPEM cells consistent with gastric mucosal regeneration.


Assuntos
Proliferação de Células , Interleucina-13 , Metaplasia , Camundongos Transgênicos , Fator de Transcrição STAT6 , Interleucina-13/metabolismo , Interleucina-13/farmacologia , Animais , Camundongos , Proliferação de Células/efeitos dos fármacos , Humanos , Fator de Transcrição STAT6/metabolismo , Mucosa Gástrica/imunologia , Mucosa Gástrica/citologia , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Organoides/metabolismo , Linfócitos/metabolismo , Linfócitos/imunologia , Linfócitos/efeitos dos fármacos , Imunidade Inata , Estômago/patologia , Estômago/citologia , Análise de Célula Única , Peptídeos e Proteínas de Sinalização Intercelular
10.
Immunohorizons ; 7(12): 842-852, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38095595

RESUMO

All cells of the immune system reside in adipose tissue (AT), and increasing type 2 immune cells may be a therapeutic strategy to improve metabolic health. In our previous study using i.p. IL-5 injections to increase eosinophils, we observed that a standard vehicle control of 0.1% BSA also elicited profound AT eosinophilia. In this study, we aimed to determine whether BSA-induced AT eosinophilia results in metabolic benefits in murine models of diet-induced obesity. I.p. 0.1% BSA injections increased AT eosinophils after 4 wk. Despite elevating eosinophils to >50% of immune cells in the AT, body weight and glucose tolerance were not different between groups. Interestingly, BSA elicited epithelial IL-33 production, as well as gene expression for type 2 cytokines and IgE production that were dependent on IL-33. Moreover, multiple models of OVA sensitization also drove AT eosinophilia. Following transplantation of a donor fat pad with BSA-induced eosinophilia, OVA-sensitized recipient mice had higher numbers of bronchoalveolar lavage eosinophils that were recipient derived. Interestingly, lungs of recipient mice contained eosinophils, macrophages, and CD8 T cells from the donor AT. These trafficked similarly from BSA- and non-BSA-treated AT, suggesting even otherwise healthy AT serves as a reservoir of immune cells capable of migrating to the lungs. In conclusion, our studies suggest that i.p. injections of BSA and OVA induce an allergic response in the AT that elicits eosinophil recruitment, which may be an important consideration for those using OVA in animal models of allergic disease.


Assuntos
Eosinofilia , Hipersensibilidade , Camundongos , Animais , Ovalbumina , Soroalbumina Bovina , Interleucina-33 , Tecido Adiposo
11.
Methods Mol Biol ; 2506: 19-41, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35771461

RESUMO

Respiratory syncytial virus (RSV) infection causes considerable mortality and morbidity in infants and young children. RSV infection appears to elicit a mixed immune response characterized by both Th1-type cells and Th2-type cells. This immune response, along with clinical features such as bronchiolitis, wheezing, and respiratory distress caused by RSV infection, presents similarly to many features of asthma and has led to an investigation into the link between severe RSV infection and asthma. RSV infection in mice is a powerful and useful tool for eliciting a Th2-type-driven immune response, lending mechanistic insight into severe RSV infection. Here we present several materials and methods used for propagating and purifying RSV, infecting mice with RSV, and analyzing samples from RSV-infected mice.


Assuntos
Asma , Infecções por Vírus Respiratório Sincicial , Animais , Asma/etiologia , Pré-Escolar , Modelos Animais de Doenças , Humanos , Camundongos , Vírus Sinciciais Respiratórios , Células Th1 , Células Th2
12.
J Clin Invest ; 132(4)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35025767

RESUMO

Women have higher prevalence of asthma compared with men. In asthma, allergic airway inflammation is initiated by IL-33 signaling through ST2, leading to increased IL-4, IL-5, and IL-13 production and eosinophil infiltration. Foxp3+ Tregs suppress and ST2+ Tregs promote allergic airway inflammation. Clinical studies showed that the androgen dehydroepiandrosterone (DHEA) reduced asthma symptoms in patients, and mouse studies showed that androgen receptor (AR) signaling decreased allergic airway inflammation. Yet the impact of AR signaling on lung Tregs remains unclear. Using AR-deficient and Foxp3 fate-mapping mice, we determined that AR signaling increased Treg suppression during Alternaria extract (Alt Ext; allergen) challenge by stabilizing Foxp3+ Tregs and limiting the number of ST2+ ex-Tregs and IL-13+ Th2 cells and ex-Tregs. AR signaling also decreased Alt Ext-induced ST2+ Tregs in mice by limiting expression of Gata2, a transcription factor for ST2, and by decreasing Alt Ext-induced IL-33 production from murine airway epithelial cells. We confirmed our findings in human cells where 5α-dihydrotestosterone (DHT), an androgen, decreased IL-33-induced ST2 expression in lung Tregs and decreased Alt Ext-induced IL-33 secretion in human bronchial epithelial cells. Our findings showed that AR signaling stabilized Treg suppressive function, providing a mechanism for the sex difference in asthma.


Assuntos
Asma/imunologia , Receptores Androgênicos/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Asma/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptores Androgênicos/genética , Transdução de Sinais/genética
13.
DNA Cell Biol ; 40(10): 1231-1234, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34265210

RESUMO

Tregulatory cells (Tregs) are an important member of the adaptive immune system and function to reduce and resolve inflammation. Prostaglandin I2 (PGI2) is a lipid mediator that has potent anti-inflammatory effects on immune cells. Several studies have investigated the interplay between PGI2 and Tregs. Together, the data from these studies demonstrate that PGI2 promotes the formation and function of Tregs. This suggests that therapeutic supplementation of PGI2 may be a treatment for various autoimmune or inflammatory diseases through enhancement of Treg function.


Assuntos
Epoprostenol/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Anti-Inflamatórios/farmacologia , Doenças Autoimunes/tratamento farmacológico , Epoprostenol/farmacologia , Epoprostenol/uso terapêutico , Humanos , Linfopoese , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos
14.
J Clin Invest ; 131(7)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33529171

RESUMO

Tregs restrain both the innate and adaptive immune systems to maintain homeostasis. Allergic airway inflammation, characterized by a Th2 response that results from a breakdown of tolerance to innocuous environmental antigens, is negatively regulated by Tregs. We previously reported that prostaglandin I2 (PGI2) promoted immune tolerance in models of allergic inflammation; however, the effect of PGI2 on Treg function was not investigated. Tregs from mice deficient in the PGI2 receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared with mice in which PGI2 signaling was intact. IP KO Tregs had significantly enhanced expression of immunoglobulin-like transcript 3 (ILT3) compared with WT Tregs, which may contribute to the impairment of the IP KO Treg's ability to suppress Th2 responses. Using fate-mapping mice, we reported that PGI2 signaling prevents Treg reprogramming toward a pathogenic phenotype. PGI2 analogs promoted the differentiation of naive T cells to Tregs in both mice and humans via repression of ß-catenin signaling. Finally, a missense variant in IP in humans was strongly associated with chronic obstructive asthma. Together, these data support that PGI2 signaling licenses Treg suppressive function and that PGI2 is a therapeutic target for enhancing Treg function.


Assuntos
Asma/imunologia , Reprogramação Celular/imunologia , Epoprostenol/imunologia , Tolerância Imunológica , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Asma/genética , Asma/patologia , Reprogramação Celular/genética , Doença Crônica , Epoprostenol/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Epoprostenol/genética , Receptores de Epoprostenol/imunologia , Transdução de Sinais/genética , Linfócitos T Reguladores/patologia
15.
Viruses ; 12(5)2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32397226

RESUMO

Respiratory syncytial virus (RSV) is a common and contagious virus that results in acute respiratory tract infections in infants. In many cases, the symptoms of RSV remain mild, however, a subset of individuals develop severe RSV-associated bronchiolitis. As such, RSV is the chief cause of infant hospitalization within the United States. Typically, the immune response to RSV is a type 1 response that involves both the innate and adaptive immune systems. However, type 2 cytokines may also be produced as a result of infection of RSV and there is increasing evidence that children who develop severe RSV-associated bronchiolitis are at a greater risk of developing asthma later in life. This review summarizes the contribution of a newly described cell type, group 2 innate lymphoid cells (ILC2), and epithelial-derived alarmin proteins that activate ILC2, including IL-33, IL-25, thymic stromal lymphopoietin (TSLP), and high mobility group box 1 (HMGB1). ILC2 activation leads to the production of type 2 cytokines and the induction of a type 2 response during RSV infection. Intervening in this innate type 2 inflammatory pathway may have therapeutic implications for severe RSV-induced disease.


Assuntos
Imunidade Inata , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Humanos , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/genética
16.
JACC Basic Transl Sci ; 5(6): 602-615, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32613146

RESUMO

Oxidative damage is implicated in atrial fibrillation (AF), but antioxidants are ineffective therapeutically. The authors tested the hypothesis that highly reactive lipid dicarbonyl metabolites, or isolevuglandins (IsoLGs), are principal drivers of AF during hypertension. In a hypertensive murine model and stretched atriomyocytes, the dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) prevented IsoLG adducts and preamyloid oligomers (PAOs), and AF susceptibility, whereas the ineffective analog 4-hydroxybenzylamine (4-HOBA) had minimal effect. Natriuretic peptides generated cytotoxic oligomers, a process accelerated by IsoLGs, contributing to atrial PAO formation. These findings support the concept of pre-emptively scavenging reactive downstream oxidative stress mediators as a potential therapeutic approach to prevent AF.

17.
Br J Pharmacol ; 176(12): 2015-2027, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29774543

RESUMO

BACKGROUND AND PURPOSE: Monocytes play a critical role in hypertension. The purpose of our study was to use an unbiased approach to determine whether hypertensive individuals on conventional therapy exhibit an altered monocyte gene expression profile and to perform validation studies of selected genes to identify novel therapeutic targets for hypertension. EXPERIMENTAL APPROACH: Next generation RNA sequencing identified differentially expressed genes in a small discovery cohort of normotensive and hypertensive individuals. Several of these genes were further investigated for association with hypertension in multiple validation cohorts using qRT-PCR, regression analysis, phenome-wide association study and case-control analysis of a missense polymorphism. KEY RESULTS: We identified 60 genes that were significantly differentially expressed in hypertensive monocytes, many of which are related to IL-1ß. Uni- and multivariate regression analyses of the expression of these genes with mean arterial pressure (MAP) revealed four genes that significantly correlated with MAP in normotensive and/or hypertensive individuals. Of these, lactoferrin (LTF), peptidoglycan recognition protein 1 and IL-18 receptor accessory protein (IL18RAP) remained significantly elevated in peripheral monocytes of hypertensive individuals in a separate validation cohort. Interestingly, IL18RAP expression associated with MAP in a cohort of African Americans. Furthermore, homozygosity for a missense single nucleotide polymorphism in LTF that decreases antimicrobial function and increases protein levels (rs1126478) was over-represented in patients with hypertension relative to controls (odds ratio 1.16). CONCLUSIONS AND IMPLICATIONS: These data demonstrate that monocytes exhibit enhanced pro-inflammatory gene expression in hypertensive individuals and identify IL18RAP and LTF as potential novel mediators of human hypertension. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Lactoferrina/farmacologia , Monócitos/metabolismo , Receptores de Interleucina-18/genética , Negro ou Afro-Americano , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/imunologia , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Humanos , Hipertensão/imunologia , Análise Multivariada , Receptores de Interleucina-18/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA
18.
JCI Insight ; 52019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31013256

RESUMO

T and B cells have been implicated in hypertension, but the mechanisms by which they produce a coordinated response is unknown. T follicular helper (Tfh) cells that produce interleukin 21 (IL21) promote germinal center (GC) B cell responses leading to immunoglobulin (Ig) production. Here we investigate the role of IL21 and Tfh cells in hypertension. In response to angiotensin (Ang) II-induced hypertension, T cell IL21 production is increased, and Il21-/- mice develop blunted hypertension, attenuated vascular end-organ damage, and decreased interleukin 17A (IL17A) and interferon gamma production. Tfh-like cells and GC B cells accumulate in the aorta and plasma IgG1 is increased in hypertensive WT but not Il21-/-mice. Furthermore, Tfh cell deficient mice develop blunted hypertension and vascular hypertrophy in response to Ang II infusion. Importantly, IL21 neutralization reduces blood pressure (BP) and reverses endothelial dysfunction and vascular inflammation. Moreover, recombinant IL21 impairs endothelium-dependent relaxation ex vivo and decreases nitric oxide production from cultured endothelial cells. Finally, we show in humans that peripheral blood T cell production of IL21 correlates with systolic BP and IL17A production. These data suggest that IL21 may be a novel therapeutic target for the treatment of hypertension and its micro- and macrovascular complications.


Assuntos
Hipertensão/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Formação de Anticorpos , Linfócitos B , Pressão Sanguínea , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Centro Germinativo , Humanos , Hipertensão/genética , Hipertensão/patologia , Imunoglobulina G , Interleucina-17 , Linfonodos/patologia , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas Recombinantes
19.
J Exp Med ; 215(1): 21-33, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29247045

RESUMO

Although systemic hypertension affects a large proportion of the population, its etiology remains poorly defined. Emerging evidence supports the concept that immune cells become activated and enter target organs, including the vasculature and the kidney, in this disease. Mediators released by these cells, including reactive oxygen species, metalloproteinases, cytokines, and antibodies promote dysfunction of the target organs and cause damage. In vessels, these factors enhance constriction, remodeling, and rarefaction. In the kidney, these mediators increase expression and activation of sodium transporters, and cause interstitial fibrosis and glomerular injury. Factors common to hypertension, including oxidative stress, increased interstitial sodium, cytokine production, and inflammasome activation promote immune activation in hypertension. Recent data suggest that isolevuglandin-modified self-proteins in antigen-presenting cells are immunogenic, promoting cytokine production by the cells in which they are formed and T cell activation. Efforts to prevent and reverse immune activation may prove beneficial in preventing the long-term sequelae of hypertension and its related cardiovascular diseases.


Assuntos
Hipertensão/etiologia , Imunidade , Animais , Microbioma Gastrointestinal , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Especificidade de Órgãos/imunologia
20.
JCI Insight ; 2(13)2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28679951

RESUMO

We previously showed that angiotensin II (Ang II) increases T cell production of IL-17A, and that mice deficient in IL-17A have blunted hypertension and attenuated renal and vascular dysfunction. It was recently shown that salt enhances IL-17A production from CD4+ T cells via a serum- and glucocorticoid-regulated kinase 1-dependent (SGK1-dependent) pathway. Thus, we tested the hypothesis that SGK1 signaling in T cells promotes hypertension and contributes to end-organ damage. We show that loss of T cell SGK1 results in a blunted hypertensive response to Ang II infusion by 25 mmHg. Importantly, renal and vascular inflammation is abrogated in these mice compared with control mice. Furthermore, mice lacking T cell SGK1 are protected from Ang II-induced endothelial dysfunction and renal injury. Loss of T cell SGK1 also blunts blood pressure and vascular inflammation in response to deoxycorticosterone acetate-salt (DOCA-salt) hypertension. Finally, we demonstrate that the Na+-K+-2Cl- cotransporter 1 (NKCC1) is upregulated in Th17 cells and is necessary for the salt-induced increase in SGK1 and the IL-23 receptor. These studies demonstrate that T cell SGK1 and NKCC1 may be novel therapeutic targets for the treatment of hypertension and identify a potentially new mechanism by which salt contributes to hypertension.

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