RESUMO
BACKGROUND: In utero exposure to heavy metals lead (Pb), mercury (Hg), and cadmium (Cd) may be associated with higher childhood blood pressure (BP), whereas trace elements selenium (Se) and manganese (Mn) may have protective antioxidant effects that modify metal-BP associations. OBJECTIVES: We examined the individual and joint effects of in utero exposure to Pb, Hg, Cd, Se, and Mn on childhood BP. METHODS: We used data from the Boston Birth Cohort (enrolled 2002-2013). We measured heavy metals and trace elements in maternal red blood cells collected 24-72 h after delivery. We calculated child BP percentile per the 2017 American Academy of Pediatrics Clinical Practice Guideline. We used linear regression models to estimate the association of each metal, and Bayesian kernel machine regression (BKMR) to examine metal coexposures, with child BP between 3 to 15 years of age. RESULTS: Our analytic sample comprised 1,194 mother-infant pairs (61% non-Hispanic Black, 20% Hispanic). Hg and Pb were not associated with child systolic BP (SBP). Se and Mn were inversely associated with child SBP percentiles, which, on average, were 6.23 points lower with a doubling of Se (95% CI: -11.51, -0.96) and 2.62 points lower with a doubling of Mn (95% CI: -5.20, -0.04). BKMR models showed similar results. Although Cd was not associated with child SBP overall, the inverse association between Mn and child SBP was stronger at higher levels of Cd (p-interaction=0.04). Consistent with this finding, in utero exposure to cigarette smoke modified the Mn-child SBP association. Among children whose mothers smoked during pregnancy, a doubling of Mn was associated with a 10.09-point reduction in SBP percentile (95% CI: -18.03, -2.15), compared with a 1.49-point reduction (95% CI: -4.21, 1.24) in children whose mothers did not smoke during pregnancy (p-interaction=0.08). CONCLUSION: Se and Mn concentrations in maternal red blood cells collected 24-72 h after delivery were associated with lower child SBP at 3 to 15 years of age. There was an interaction between Mn and Cd on child SBP, whereby the protective association of Mn on child SBP was stronger among mothers who had higher Cd. The association of Mn and child SBP was also modified by maternal cigarette smoking-a source of Cd-during pregnancy. Optimizing in utero Se levels, as well as Mn levels in women who had high Cd or smoked during pregnancy, may protect offspring from developing high BP during childhood. https://doi.org/10.1289/EHP8325.
Assuntos
Metais Pesados , Selênio , Oligoelementos , Teorema de Bayes , Pressão Sanguínea , Criança , Feminino , Humanos , Metais Pesados/toxicidade , GravidezRESUMO
The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1-FPR2-IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces.
Assuntos
Asma/imunologia , Rinite Alérgica/imunologia , Proteína Amiloide A Sérica/metabolismo , Transdução de Sinais/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alérgenos/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Asma/patologia , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais , Proteínas de Ligação a Ácido Graxo/imunologia , Feminino , Humanos , Imunidade Humoral , Imunidade Inata , Interleucina-33/metabolismo , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Cultura Primária de Células , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Rinite Alérgica/patologia , Proteína Amiloide A Sérica/genética , Regulação para Cima , Adulto JovemRESUMO
Aberrant type 2 responses underlie the pathologies in allergic diseases like asthma, yet, our understanding of the mechanisms that drive them remains limited. Recent evidence suggests that dysregulated innate immune factors can perpetuate asthma pathogenesis. In susceptible individuals, allergen exposure triggers the activation of complement, a major arm of innate immunity, leading to the aberrant generation of the C3a anaphylatoxin. C3 and C3a have been shown to be important for the development of Th2 responses, yet remarkably, the mechanisms by which C3a regulates type 2 immunity are relatively unknown. We demonstrate a central role for C3a in driving type 2 innate lymphoid cells (ILC2)-mediated inflammation in response to allergen and IL-33. Our data suggests that ILC2 recruitment is C3a-dependent. Further, we show that ILC2s directly respond to C3a, promoting type 2 responses by specifically: (1) inducing IL-13 and granulocyte-macrophage colony-stimulating factor, whereas inhibiting IL-10 production from ILC2; and (2) enhancing their antigen-presenting capability during ILC-T-cell cross-talk. In summary, we identify a novel mechanism by which C3a can mediate aberrant type 2 responses to aeroallergen exposure, which involves a yet unrecognized cross-talk between two major innate immune components-complement and group 2 innate lymphoid cells.
Assuntos
Asma/imunologia , Complemento C3a/metabolismo , Hipersensibilidade/imunologia , Inflamação/imunologia , Linfócitos/imunologia , Sistema Respiratório/imunologia , Células Th2/imunologia , Alérgenos/imunologia , Animais , Apresentação de Antígeno , Comunicação Celular , Movimento Celular , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Imunidade Inata , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-33/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Intestinal segmented filamentous bacteria (SFB) protect from ameba infection, and protection is transferable with bone marrow dendritic cells (BMDCs). SFB cause an increase in serum amyloid A (SAA), suggesting that SAA might mediate SFB's effects on BMDCs. Here we further explored the role of bone marrow in SFB-mediated protection. Transient gut colonization with SFB or SAA administration alone transiently increased the H3K27 histone demethylase Jmjd3, persistently increased bone marrow Csf2ra expression and granulocyte monocyte precursors (GMPs), and protected from ameba infection. Pharmacologic inhibition of Jmjd3 H3K27 demethylase activity during SAA treatment or blockade of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling in SFB-colonized mice prevented GMP expansion, decreased gut neutrophils, and blocked protection from ameba infection. These results indicate that alteration of the microbiota and systemic exposure to SAA can influence myelopoiesis and susceptibility to amebiasis via epigenetic mechanisms. Gut microbiota-marrow communication is a previously unrecognized mechanism of innate protection from infection.
Assuntos
Células da Medula Óssea/citologia , Entamoeba histolytica/fisiologia , Entamebíase/fisiopatologia , Trato Gastrointestinal/microbiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Proteína Amiloide A Sérica/fisiologia , Animais , Bactérias , Medula Óssea/metabolismo , Células da Medula Óssea/fisiologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Células Progenitoras de Granulócitos e Macrófagos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismoRESUMO
BACKGROUND: Serum caffeine concentrations >20 µg/ml (100 µmol/l) in infants treated for apnea of prematurity increases TNF-α and decreases IL-10, changes that perhaps are linked to comorbidities. We hypothesize that this proinflammatory cytokine profile may be linked to differential binding of caffeine to adenosine receptor subtypes (AR), inhibition of phosphodiesterases (PDEs), and modulation of toll-like receptors (TLR). METHODS: Lipopolysaccharide-activated cord blood monocytes (CBM) from 19 infants were exposed to caffeine (0-200 µmol/l) with or without previous exposure to A1R, A3R, or PDE IV antagonists to determine changes in dose-response curves. Cytokines levels (enzyme-linked immunosorbent assay (ELISA)), intracellular cyclic adenosine monophosphate (cAMP) accumulation (enzyme immunoassay (EIA)), and TLR gene expression (real time qRT PCR) were measured. RESULTS: Caffeine at ≤100 µmol/l decreased TNF-α levels (~25%, P = 0.01) and cAMP. All caffeine concentrations decreased IL-10 levels (17-35%, P < 0.01). A1R, A3R, and PDE blockades decreased TNF-α (31, 21, and 88%, P ≤ 0.01), but not IL-10. Caffeine further decreased TNF-α following A3R and PDE blockades. Caffeine concentrations directly correlated to TLR4 gene expression (r = 0.84; P < 0.001). CONCLUSION: Neither A3R, nor PDE blockades are involved in caffeine's modulation of cytokine release by CBM at any concentration. Besides A1R blockade, caffeine's upregulation of TLR4 may promote inflammation at high concentrations.
Assuntos
Apneia/tratamento farmacológico , Cafeína/farmacologia , Citocinas/metabolismo , Sangue Fetal/efeitos dos fármacos , Regulação da Expressão Gênica , Monócitos/efeitos dos fármacos , Índice de Apgar , Apneia/sangue , Estimulantes do Sistema Nervoso Central/farmacologia , Comorbidade , AMP Cíclico/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Inflamação , Interleucina-10/sangue , Lipopolissacarídeos , Masculino , Diester Fosfórico Hidrolases/metabolismo , Receptores Purinérgicos P1/metabolismo , Transcrição Gênica , Fator de Necrose Tumoral alfa/sangueRESUMO
Aberrant production of the prototypical type 2 cytokines, interleukin (IL)-4 and IL-13 has long been associated with the pathogenesis of allergic disorders. Despite tremendous scientific inquiry, the similarities in their structure, and receptor usage have made it difficult to ascertain the distinct role that these two look-alike cytokines play in the onset and perpetuation of allergic inflammation. However, recent discoveries of differences in receptor distribution, utilization/assembly and affinity between IL-4 and IL-13, along with the discovery of unique innate lymphoid 2 cells (ILC2) which preferentially produce IL-13, not IL-4, are beginning to shed light on these mysteries. The purpose of this chapter is to review our current understanding of the distinct roles that IL-4 and IL-13 play in allergic inflammatory states and the utility of their modulation as potential therapeutic strategies for the treatment of allergic disorders.
Assuntos
Asma/imunologia , Hipersensibilidade/imunologia , Interleucina-13/imunologia , Interleucina-4/imunologia , Animais , Ensaios Clínicos como Assunto , Citocinas/imunologia , Modelos Animais de Doenças , Células Epiteliais/imunologia , Fibrose/metabolismo , Humanos , Imunidade Inata , Inflamação , Linfócitos/imunologia , Macrófagos/imunologia , Camundongos , Ligação Proteica , Sistema Respiratório/imunologia , Transdução de SinaisRESUMO
Allergic asthma is a chronic inflammatory disorder that affects â¼20% of the population worldwide. Microarray analyses of nasal epithelial cells from acute asthmatic patients detected a 50% decrease in expression of Stard7, an intracellular phosphatidylcholine transport protein. To determine whether loss of Stard7 expression promotes allergic responses, mice were generated in which one allele of the Stard7 locus was globally disrupted (Stard7 (+/-) mice). OVA sensitization and challenge of Stard7(+/-) mice resulted in a significant increase in pulmonary inflammation, mucous cell metaplasia, airway hyperresponsiveness, and OVA-specific IgE compared with OVA-sensitized/challenged wild-type (WT) mice. This exacerbation was largely Th2-mediated with a significant increase in CD4(+)IL-13(+) T cells and IL-4, IL-5, and IL-13 cytokines. The loss of Stard7 was also associated with increased lung epithelial permeability and activation of proinflammatory dendritic cells in sensitized and/or challenged Stard7 (+/-) mice. Notably, OVA-pulsed dendritic cells from Stard7(+/-) mice were sufficient to confer an exaggerated allergic response in OVA-challenged WT mice, although airway hyperresponsiveness was greater in Stard7(+/-) recipients compared with WT recipients. Enhanced allergic responses in the lung were accompanied by age-dependent development of spontaneous atopic dermatitis. Overall, these data suggest that Stard7 is an important component of a novel protective pathway in tissues exposed to the extracellular environment.
Assuntos
Proteínas de Transporte/genética , Haploinsuficiência , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Pulmão/imunologia , Pele/imunologia , Transferência Adotiva , Animais , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Dermatite/genética , Dermatite/imunologia , Dermatite/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Deleção de Genes , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , Ovalbumina/efeitos adversos , Ovalbumina/imunologia , Permeabilidade , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Pele/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
High levels of the intermediate filament keratin 17 (K17) correlate with a poor prognosis for several types of epithelial tumors. However, the causal relationship and underlying mechanisms remain undefined. A recent study suggested that K17 promotes skin tumorigenesis by fostering a specific type of inflammation. We report here that K17 interacts with the RNA-binding protein hnRNP K, which has also been implicated in cancer. K17 is required for the cytoplasmic localization of hnRNP K and for its role in regulating the expression of multiple pro-inflammatory mRNAs. Among these are the CXCR3 ligands CXCL9, CXCL10, and CXCL11, which together form a signaling axis with an established role in tumorigenesis. The K17-hnRNP K partnership is regulated by the ser/thr kinase RSK and required for CXCR3-dependent tumor cell growth and invasion. These findings functionally integrate K17, hnRNP K, and gene expression along with RSK and CXCR3 signaling in a keratinocyte-autonomous axis and provide a potential basis for their implication in tumorigenesis.
Assuntos
Quimiocinas CXC/biossíntese , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Queratinócitos/metabolismo , Queratinas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Quimiocinas CXC/genética , Células HeLa , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Humanos , Queratinas/genética , Camundongos Knockout , Proteínas de Neoplasias/genética , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Transdução de Sinais/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
Activation of the complement system has long been known to be regulated by a series of steps involving fluid-phase convertases. In this issue of Immunity, Liszewski et al. (2013) report the discovery of an intracellular cathepsin-L-dependent C3 activation pathway.
Assuntos
Subpopulações de Linfócitos B/citologia , Linfócitos T CD4-Positivos/imunologia , Catepsina L/metabolismo , Diferenciação Celular , Ativação do Complemento/fisiologia , Complemento C3/metabolismo , Homeostase/fisiologia , HumanosRESUMO
The molecular mechanisms that drive mucosal T helper type 2 (T(H)2) responses against parasitic helminths and allergens remain unclear. In this study, we demonstrate in mice that TFF2 (trefoil factor 2), an epithelial cell-derived repair molecule, is needed for the control of lung injury caused by the hookworm parasite Nippostrongylus brasiliensis and for type 2 immunity after infection. TFF2 is also necessary for the rapid production of IL-33, a T(H)2-promoting cytokine, by lung epithelia, alveolar macrophages, and inflammatory dendritic cells in infected mice. TFF2 also increases the severity of allergic lung disease caused by house dust mite antigens or IL-13. Moreover, TFF2 messenger RNA expression is significantly increased in nasal mucosal brushings during asthma exacerbations in children. These experiments extend the biological functions of TFF2 from tissue repair to the initiation and maintenance of mucosal T(H)2 responses.
Assuntos
Asma/imunologia , Infecções por Uncinaria/imunologia , Interleucinas/biossíntese , Mucinas/imunologia , Proteínas Musculares/imunologia , Peptídeos/imunologia , Animais , Criança , Humanos , Imunidade nas Mucosas , Interleucina-33 , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucinas/deficiência , Mucinas/genética , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Nippostrongylus , Peptídeos/deficiência , Peptídeos/genética , RNA Mensageiro/genética , Células Th2/imunologia , Fator Trefoil-2RESUMO
BACKGROUND: A common characteristic of allergens is that they contain proteases that can activate protease-activated receptor (PAR-2); however the mechanism by which PAR-2 regulates allergic airway inflammation is unclear. METHODS: Mice (wild type and PAR-2-deficient) were sensitized using German cockroach (GC) feces (frass), the isolated protease from GC frass, or through adoptive transfer of GC frass-treated bone marrow-derived dendritic cells (BMDC) and measurements of airway inflammation (cellular infiltration, cytokine expression, and mucin production), serum IgE levels and airway hyperresponsiveness (AHR) were assessed. BMDC were cultured, treated with GC frass and assessed for cytokine production. PAR-2 expression on pulmonary mDCs was determined by flow cytometry. RESULTS: Exposure to GC frass induced AHR and airway inflammation in wild type mice; however PAR-2-deficient mice had significantly attenuated responses. To directly investigate the role of the protease, we isolated the protease from GC frass and administered the endotoxin-free protease into the airways of mice in the presence of OVA. GC frass proteases were sufficient to promote the development of AHR, serum IgE, and Th2 cytokine production. PAR-2 expression on mDC was upregulated following GC frass exposure, but the presence of a functional PAR-2 did not alter antigen uptake. To determine if PAR-2 activation led to differential cytokine production, we cultured BMDC in the presence of GM-CSF and treated these cells ex vivo with GC frass. PAR-2-deficient BMDC released significantly less IL-6, IL-23 and TNFα compared to BMDC from wild type mice, suggesting PAR-2 activation was important in Th2/Th17 skewing cytokine production. To determine the role for PAR-2 on mDCs on the initiation of allergic airway inflammation, BMDCs from wild type and PAR-2-deficient mice were treated in the presence or absence of GC frass and then adoptively transferred into the airway of wild type mice. Importantly, GC frass-stimulated wild type BMDCs were sufficient to induce AHR and allergic airway inflammation, while GC frass-stimulated PAR-2-deficient BMDC had attenuated responses. CONCLUSIONS: Together these data suggest an important role for allergen activation of PAR-2 on mDCs in mediating Th2/Th17 cytokine production and allergic airway responses.
Assuntos
Células Dendríticas/patologia , Mediadores da Inflamação/fisiologia , Células Mieloides/patologia , Receptor PAR-2/fisiologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Animais , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Células Cultivadas , Baratas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptor PAR-2/deficiência , Receptor PAR-2/genética , Hipersensibilidade Respiratória/imunologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologiaRESUMO
Myeloid cells are a feature of most tissues. Here we show that during development, retinal myeloid cells (RMCs) produce Wnt ligands to regulate blood vessel branching. In the mouse retina, where angiogenesis occurs postnatally, somatic deletion in RMCs of the Wnt ligand transporter Wntless results in increased angiogenesis in the deeper layers. We also show that mutation of Wnt5a and Wnt11 results in increased angiogenesis and that these ligands elicit RMC responses via a non-canonical Wnt pathway. Using cultured myeloid-like cells and RMC somatic deletion of Flt1, we show that an effector of Wnt-dependent suppression of angiogenesis by RMCs is Flt1, a naturally occurring inhibitor of vascular endothelial growth factor (VEGF). These findings indicate that resident myeloid cells can use a non-canonical, Wnt-Flt1 pathway to suppress angiogenic branching.
Assuntos
Células Mieloides/metabolismo , Neovascularização Fisiológica/fisiologia , Retina/citologia , Transdução de Sinais , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Wnt/metabolismo , Animais , Vasos Sanguíneos/crescimento & desenvolvimento , Células Endoteliais/metabolismo , Fibroblastos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Ligantes , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Camundongos , Receptores Acoplados a Proteínas G , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Proteínas Wnt/deficiência , Proteínas Wnt/genética , Proteína Wnt-5aRESUMO
BACKGROUND: Glutathione S-transferase pi (GSTPi) is the predominant redox regulator in the lung. Although evidence implicates an important role for GSTPi in asthma, the mechanism for this has remained elusive. OBJECTIVES: We sought to determine how GSTPi is regulated in asthma and to elucidate its role in maintaining redox homeostasis. METHODS: We elucidated the regulation of GSTPi in children with asthma and used murine models of asthma to determine the role of GSTPi in redox homeostasis. RESULTS: Our findings demonstrate that GSTPi transcript levels are markedly downregulated in allergen- and IL-13-treated murine models of asthma through signal transducer and activator of transcription 6-dependent and independent pathways. Nuclear factor erythroid 2-related factor 2 was also downregulated in these models. The decrease in GSTPi expression was associated with decreased total glutathione S-transferase activity in the lungs of mice. Examination of cystine intermediates uncovered a functional role for GSTPi in regulating cysteine oxidation, whereby GSTPi-deficient mice exhibited increased oxidative stress (increase in percentage cystine) compared with wild-type mice after allergen challenge. GSTPi expression was similarly downregulated in children with asthma. CONCLUSIONS: These data collectively suggest that downregulation of GSTPi after allergen challenge might contribute to the asthma phenotype because of disruption of redox homeostasis and increased oxidative stress. Furthermore, GSTPi might be an important therapeutic target for asthma, and evaluation of GSTPi expression might prove beneficial in identifying patients who would benefit from therapy targeting this pathway.
Assuntos
Asma/fisiopatologia , Regulação para Baixo , Glutationa S-Transferase pi/metabolismo , Estresse Oxidativo/fisiologia , Adolescente , Alérgenos/imunologia , Animais , Asma/metabolismo , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Glutationa S-Transferase pi/genética , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Oxirredução , Transdução de Sinais , Testes CutâneosRESUMO
OBJECTIVE: To determine changes in cytokine levels associated with caffeine treatment in a cohort of preterm infants. STUDY DESIGN: For this observational prospective study, we collected clinical data from 26 preterm infants (≤ 30 weeks gestational age). In addition to caffeine levels, cytokine profiles in peripheral blood (PB) and tracheal aspirates (TA) were determined with enzyme-linked immunosorbent assay at birth, before and after (at 24 hours and 1 week) initiation of caffeine. Non-parametric statistics were applied. RESULTS: Included infants were 26.9 ± 1.7 weeks gestational age and weighed 985 ± 202 g. At birth, all cytokine concentrations were significantly greater in TA than PB. Serum caffeine levels were 11.1 µg/mL (interquartile range, 1.85) at approximately 24 hours post-load and 16.4 (8.7) µg/mL at 1 week on treatment. At approximately 24 hours post-load, interleukin (IL)-10 levels decreased by 47.5% (P = .01) in PB and 38.5% (P = .03) in TA, whereas other cytokine levels remained unchanged. At 1 week, caffeine levels were correlated (U-shaped) with changes in proinflammatory tumor necrosis factor-α (R(2) = 0.65; P = .0008), interleukin (IL)-1ß (R(2) = 0.73; P = .0007), and IL-6 (R(2) = 0.59; P = .003), whereas inversely correlated (linear) with the anti-inflammatory IL-10 (R(2) = 0.64; P = .0008). Altogether, caffeine, at serum levels ≥ 20 µg/mL, was associated with a proinflammatory profile after 1 week of treatment. CONCLUSIONS: Caffeine treatment for apnea of prematurity correlates with changes in cytokine profile. Caffeine levels ≥ 20 µg/mL are associated with a proinflammatory profile in our cohort of preterm infants.
Assuntos
Cafeína/sangue , Citocinas/sangue , Recém-Nascido Prematuro/sangue , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Asthma is a major public health burden worldwide. Studies from our group and others have demonstrated that SERPINB3 and SERPINB4 are induced in patients with asthma; however, their mechanistic role in asthma has yet to be determined. OBJECTIVE: To evaluate the role of Serpin3a, the murine homolog of SERPINB3 and SERPINB4, in asthma. METHODS: We studied wild-type Balb/c and Serpinb3a-null mice in house dust mite or IL-13-induced asthma models and evaluated airway hyperresponsiveness, inflammation, and goblet cell hyperplasia. RESULTS: Airway hyperresponsiveness and goblet cell hyperplasia were markedly attenuated in the Serpinb3a-null mice compared with the wild-type mice after allergen challenge, with minimal effects on inflammation. Expression of sterile alpha motif pointed domain containing v-ets avian erythroblastosis virus E26 oncogene homolog transcription factor (SPDEF), a transcription factor that mediates goblet cell hyperplasia, was decreased in the absence of Serpinb3a. IL-13-treated Serpinb3a-null mice showed attenuated airway hyperresponsiveness, inflammation, and mucus production. CONCLUSION: Excessive mucus production and mucus plugging are key pathologic features of asthma, yet the mechanisms responsible for mucus production are not well understood. Our data reveal a novel nonredundant role for Serpinb3a in mediating mucus production through regulation of SPDEF expression. This pathway may be used to target mucus hypersecretion effectively.
Assuntos
Asma/imunologia , Muco/imunologia , Proteínas Proto-Oncogênicas c-ets/imunologia , Serpinas/imunologia , Animais , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar , Separação Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Expressão Gênica , Regulação da Expressão Gênica/imunologia , Células Caliciformes/imunologia , Células Caliciformes/metabolismo , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Muco/metabolismo , Proteínas Proto-Oncogênicas c-ets/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serpinas/metabolismoRESUMO
Programmed cell death-1 (PD-1) is a newly characterized negative regulator of immune responses. The interaction of PD-1 with its ligands (PD-L1 and PD-L2) inhibits T-cell proliferation and cytokine production in young mice. Increased PD-1 expression has been described during chronic infections, inducing chronic activation of the immune system to control it. As aging is associated with chronic immune activation, PD-1 may contribute to age-associated T-cell dysfunction. Our data showed the following results in aged mice: (i) the number of PD-1-expressing T cells and the level of expression of PD-Ls was increased on dendritic cell subsets and T cells; (ii) PD-1(+) T cells were exhausted effector memory T cells, as shown by their lower level of CD127, CD25 and CD28, as well as their limited proliferative and cytokine-producing capacity; (iii) the expression of PD-1 was up-regulated after T-cell receptor-mediated activation of CD8(+) T cells, but not of CD4(+) T cells; (iv) blockade of the PD-1/PD-L1 pathway moderately improved the cytokine production of T cells from old mice but did not restore their proliferation; and (v) blockade of the PD-1/PD-L1 pathway did not restore function of PD-1(+) T cells; its effect appeared to be exclusively mediated by increased functionality of the PD-1(-) T cells. Our data thus suggest that blockade of the PD-1/PD-L1 is not likely to be efficient at restoring exhausted T-cell responses in aged hosts, although improving the responses of PD-1(-) T cells may prove to be a helpful strategy in enhancing primary responses.
Assuntos
Envelhecimento , Antígenos de Superfície/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Antígeno B7-1/metabolismo , Glicoproteínas de Membrana/metabolismo , Peptídeos/metabolismo , Linfócitos T/metabolismo , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Antígeno B7-H1 , Proliferação de Células/efeitos dos fármacos , Citocinas/análise , Citocinas/biossíntese , Citometria de Fluxo , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/antagonistas & inibidores , Receptor de Morte Celular Programada 1RESUMO
BACKGROUND: Allergic asthma is on the rise in developed countries. A common characteristic of allergens is that they contain intrinsic protease activity, and many have been shown to activate protease-activated receptor (PAR)-2 in vitro. The role for PAR-2 in mediating allergic airway inflammation has not been assessed using a real world allergen. METHODS: Mice (wild type or PAR-2-deficient) were sensitized to German cockroach (GC) feces (frass) or protease-depleted GC frass by either mucosal exposure or intraperitoneal injection and measurements of airway inflammation (IL-5, IL-13, IL-17A, and IFNgamma levels in the lung, serum IgE levels, cellular infiltration, mucin production) and airway hyperresponsiveness were performed. RESULTS: Following systemic sensitization, GC frass increased airway hyperresponsiveness, Th2 cytokine release, serum IgE levels, cellular infiltration and mucin production in wild type mice. Interestingly, PAR-2-deficient mice had similar responses as wild type mice. Since these data were in direct contrast to our finding that mucosal sensitization with GC frass proteases regulated airway hyperresponsiveness and mucin production in BALB/c mice (Page et. al. 2007 Resp Res 8:91), we backcrossed the PAR-2-deficient mice into the BALB/c strain. Sensitization to GC frass could now occur via the more physiologically relevant method of intratracheal inhalation. PAR-2-deficient mice had significantly reduced airway hyperresponsiveness, Th2 and Th17 cytokine release, serum IgE levels, and cellular infiltration compared to wild type mice when sensitization to GC frass occurred through the mucosa. To confirm the importance of mucosal exposure, mice were systemically sensitized to GC frass or protease-depleted GC frass via intraperitoneal injection. We found that removal of proteases from GC frass had no effect on airway inflammation when administered systemically. CONCLUSIONS: We showed for the first time that allergen-derived proteases in GC frass elicit allergic airway inflammation via PAR-2, but only when allergen was administered through the mucosa. Importantly, our data suggest the importance of resident airway cells in the initiation of allergic airway disease, and could make allergen-derived proteases attractive therapeutic targets.
Assuntos
Alérgenos , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Baratas/imunologia , Imunidade nas Mucosas , Proteínas de Insetos/imunologia , Pulmão/imunologia , Peptídeo Hidrolases/imunologia , Receptor PAR-2/metabolismo , Administração por Inalação , Alérgenos/administração & dosagem , Animais , Asma/metabolismo , Asma/fisiopatologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Baratas/enzimologia , Fezes/enzimologia , Imunoglobulina E/sangue , Injeções Intraperitoneais , Proteínas de Insetos/administração & dosagem , Interferon gama/metabolismo , Interleucina-13/metabolismo , Interleucina-17/metabolismo , Interleucina-5/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucinas/metabolismo , Peptídeo Hidrolases/administração & dosagem , Receptor PAR-2/deficiência , Receptor PAR-2/genética , Especificidade da EspécieRESUMO
After birth, the respiratory tract adapts to recurrent exposures to pathogens, allergens, and toxicants by inducing the complex innate and acquired immune systems required for pulmonary homeostasis. In this study, we show that Foxa2, expressed selectively in the respiratory epithelium, plays a critical role in regulating genetic programs influencing Th2 cell-mediated pulmonary inflammation. Deletion of the Foxa2 gene, encoding a winged helix/forkhead box transcription factor that is selectively expressed in respiratory epithelial cells, caused spontaneous pulmonary eosinophilic inflammation and goblet cell metaplasia. Loss of Foxa2 induced the recruitment and activation of myeloid dendritic cells and Th2 cells in the lung, causing increased production of Th2 cytokines and chemokines. Loss of Foxa2-induced expression of genes regulating Th2 cell-mediated inflammation and goblet cell differentiation, including IL-13, IL-4, eotaxins, thymus and activation-regulated chemokine, Il33, Ccl20, and SAM pointed domain-containing Ets transcription factor. Pulmonary inflammation and goblet cell differentiation were abrogated by treatment of neonatal Foxa2(Delta/Delta) mice with mAb against IL-4Ralpha subunit. The respiratory epithelium plays a central role in the regulation of Th2-mediated inflammation and innate immunity in the developing lung in a process regulated by Foxa2.
Assuntos
Fator 3-beta Nuclear de Hepatócito/imunologia , Imunidade Inata/imunologia , Pulmão/crescimento & desenvolvimento , Pulmão/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Separação Celular , Citometria de Fluxo , Expressão Gênica , Regulação da Expressão Gênica/imunologia , Células Caliciformes/citologia , Fator 3-beta Nuclear de Hepatócito/genética , Imunidade nas Mucosas/genética , Imunidade nas Mucosas/imunologia , Imuno-Histoquímica , Inflamação/genética , Inflamação/imunologia , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/análise , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Arginase is significantly upregulated in the lungs in murine models of asthma, as well as in human asthma, but its role in allergic airway inflammation has not been fully elucidated in mice. RESULTS: In order to test the hypothesis that arginase has a role in allergic airway inflammation we generated arginase I-deficient bone marrow (BM) chimeric mice. Following transfer of arginase I-deficient BM into irradiated recipient mice, arginase I expression was not required for hematopoietic reconstitution and baseline immunity. Arginase I deficiency in bone marrow-derived cells decreased allergen-induced lung arginase by 85.8 +/- 5.6%. In contrast, arginase II-deficient mice had increased lung arginase activity following allergen challenge to a similar level to wild type mice. BM-derived arginase I was not required for allergen-elicited sensitization, recruitment of inflammatory cells in the lung, and proliferation of cells. Furthermore, allergen-induced airway hyperresponsiveness and collagen deposition were similar in arginase-deficient and wild type mice. Additionally, arginase II-deficient mice respond similarly to their control wild type mice with allergen-induced inflammation, airway hyperresponsiveness, proliferation and collagen deposition. CONCLUSION: Bone marrow cell derived arginase I is the predominant source of allergen-induced lung arginase but is not required for allergen-induced inflammation, airway hyperresponsiveness or collagen deposition.
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Alérgenos/imunologia , Arginase , Células da Medula Óssea/enzimologia , Pulmão/metabolismo , Quimera por Radiação , Hipersensibilidade Respiratória/enzimologia , Animais , Arginase/imunologia , Células da Medula Óssea/patologia , Transplante de Medula Óssea , Colágeno/metabolismo , Hiperargininemia , Imunização , Inflamação , Pulmão/imunologia , Pulmão/patologia , Camundongos , Hipersensibilidade Respiratória/patologiaRESUMO
The role of complement in the development of maladaptive immunity in experimental allergic asthma is unclear. In this study, we show that C3a receptor (C3aR)-deficient mice are protected from the development of Th2 immunity in a model of house dust mite-induced asthma. C5a receptor (C5aR)-targeting of C3aR-deficient mice during allergen sensitization not only reversed the protective effect but enhanced Th2 cytokine production, airway inflammation, and airway responsiveness, suggesting that the reduced allergic phenotype in C3aR-deficient mice results from protective C5aR signaling. In support of this view, C5aR expression in C3aR-deficient pulmonary dendritic cells (DCs) was increased when compared with wild-type DCs. Moreover, C5aR targeting regulated the frequency of pulmonary plasmacytoid DCs expressing costimulatory molecules B7-H1 and B7-DC. Ex vivo targeting of B7-H1 and B7-DC increased Th2 cytokine production from T cells of wild-type but not of C5aR-targeted mice, suggesting a protective role for C5a through regulation of B7 molecule expression on plasmacytoid DCs.