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1.
Annu Rev Immunol ; 28: 367-88, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20192808

RESUMO

The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders. HMGB1 can associate with other molecules, including TLR ligands and cytokines, and activates cells through the differential engagement of multiple surface receptors including TLR2, TLR4, and RAGE. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-beta. RAGE activation has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease. While HMGB1 through interactions with TLRs may also be important, this review focuses on the role of the HMGB1-RAGE axis in inflammation and cancer.


Assuntos
Proteína HMGB1/imunologia , Inflamação/imunologia , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Animais , Proteína HMGB1/química , Humanos , Inflamação/metabolismo , Ligantes , Neoplasias/metabolismo , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/metabolismo , Transdução de Sinais
2.
Immunity ; 37(6): 986-997, 2012 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23219390

RESUMO

Toll-like receptor-9 (TLR9) is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the pathogenic secretion of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Here, we found that in response to DNA-containing immune complexes (DNA-IC), but not to soluble ligands, IFN-α production depended upon the convergence of the phagocytic and autophagic pathways, a process called microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP). LAP was required for TLR9 trafficking into a specialized interferon signaling compartment by a mechanism that involved autophagy-related proteins, but not the conventional autophagic preinitiation complex, or adaptor protein-3 (AP-3). Our findings unveil a new role for nonconventional autophagy in inflammation and provide one mechanism by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict the apportionment of pathogenic DNA and TLR9 to the interferon signaling compartment.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Autofagia/imunologia , DNA/imunologia , Interferon Tipo I/biossíntese , Animais , Humanos , Imunoglobulina G/imunologia , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Fagocitose/imunologia , Fagossomos/metabolismo , Transporte Proteico , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismo
3.
J Biol Chem ; 293(9): 3039-3055, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29317497

RESUMO

Slit guidance ligand 2 (SLIT2) is a large, secreted protein that binds roundabout (ROBO) receptors on multiple cell types, including neurons and kidney podocytes. SLIT2-ROBO-mediated signaling regulates neuronal migration and ureteric bud (UB) outgrowth during kidney development as well as glomerular filtration in adult kidneys. Additionally, SLIT2 binds Gremlin, an antagonist of bone morphogenetic proteins (BMPs), and BMP-Gremlin signaling also regulates UB formation. However, direct cross-talk between the ROBO2-SLIT2 and BMP-Gremlin signaling pathways has not been established. Here, we report the discovery of negative feedback between the SLIT2 and BMP-Gremlin signaling pathways. We found that the SLIT2-Gremlin interaction inhibited both SLIT2-ROBO2 signaling in neurons and Gremlin antagonism of BMP activity in myoblasts and fibroblasts. Furthermore, BMP2 down-regulated SLIT2 expression and promoter activity through canonical BMP signaling. Gremlin treatment, BMP receptor inhibition, and SMAD family member 4 (SMAD4) knockdown rescued BMP-mediated repression of SLIT2. BMP2 treatment of nephron progenitor cells derived from human embryonic stem cells decreased SLIT2 expression, further suggesting an interaction between the BMP2-Gremlin and SLIT2 pathways in human kidney cells. In conclusion, our study has revealed direct negative cross-talk between two pathways, previously thought to be unassociated, that may regulate both kidney development and adult tissue maintenance.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais , Proteína Morfogenética Óssea 2/farmacologia , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Retroalimentação Fisiológica/efeitos dos fármacos , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Neurônios/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Domínios Proteicos , Transdução de Sinais/efeitos dos fármacos
4.
J Immunol ; 197(1): 42-50, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27226090

RESUMO

Type I IFNs play a critical role in the immune response to viral infection and may also drive autoimmunity through modulation of monocyte maturation and promotion of autoreactive lymphocyte survival. Recent demonstrations of type I IFN gene signatures in autoimmune diseases, including scleroderma, led us to investigate the pathological role of IFNs in a preclinical model of sclerodermatous graft-versus-host disease. Using a neutralizing Ab against the type I IFN receptor IFNAR1, we observed a marked reduction in dermal inflammation, vasculopathy, and fibrosis compared with that seen in the presence of intact IFNAR1 signaling. The ameliorative effects of IFNAR1 blockade were restricted to the skin and were highly associated with inhibition of chronic vascular injury responses and not due to the inhibition of the T or B cell alloresponse. Inhibition of IFNAR1 normalized the overexpression of IFN-inducible genes in graft-versus-host disease skin and markedly reduced dermal IFN-α levels. Depletion of plasmacytoid dendritic cells, a major cellular source of type I IFNs, did not reduce the severity of fibrosis or type I IFN gene signature in the skin. Taken together, these studies demonstrate an important role for type I IFN in skin fibrosis, and they provide a rationale for IFNAR1 inhibition in scleroderma.


Assuntos
Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Inflamação/imunologia , Interferon-alfa/metabolismo , Escleroderma Sistêmico/imunologia , Pele/patologia , Doenças Vasculares/imunologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Autoanticorpos/sangue , Modelos Animais de Doenças , Feminino , Fibrose , Regulação da Expressão Gênica , Humanos , Interferon-alfa/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais
5.
J Biol Chem ; 291(5): 2435-43, 2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26631728

RESUMO

The Wnt family of secreted glycolipoproteins plays pivotal roles in development and human diseases. Tiki family proteins were identified as novel Wnt inhibitors that act by cleaving the Wnt amino-terminal region to inactivate specific Wnt ligands. Tiki represents a new metalloprotease family that is dependent on Mn(2+)/Co(2+) but lacks known metalloprotease motifs. The Tiki extracellular domain shares homology with bacterial TraB/PrgY proteins, known for their roles in the inhibition of mating pheromones. The TIKI/TraB fold is predicted to be distantly related to structures of additional bacterial proteins and may use a core ß-sheet within an α+ß-fold to coordinate conserved residues for catalysis. In this study, using assays for Wnt3a cleavage and signaling inhibition, we performed mutagenesis analyses of human TIKI2 to examine the structural prediction and identify the active site residues. We also established an in vitro assay for TIKI2 protease activity using FRET peptide substrates derived from the cleavage motifs of Wnt3a and Xenopus wnt8 (Xwnt8). We further identified two pairs of potential disulfide bonds that reside outside the ß-sheet catalytic core but likely assist the folding of the TIKI domain. Finally, we systematically analyzed TIKI2 cleavage of the 19 human WNT proteins, of which we identified 10 as potential TIKI2 substrates, revealing the hydrophobic nature of Tiki cleavage sites. Our study provides insights into the Tiki family of proteases and its Wnt substrates.


Assuntos
Regulação Enzimológica da Expressão Gênica , Metaloendopeptidases/química , Proteínas Wnt/química , Motivos de Aminoácidos , Animais , Domínio Catalítico , Cisteína/química , Dissulfetos/química , Transferência Ressonante de Energia de Fluorescência , Células HEK293 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Luciferases/metabolismo , Proteínas de Membrana/química , Metaloproteases/química , Mutagênese Sítio-Dirigida , Peptídeos/química , Feromônios Humano/metabolismo , Dobramento de Proteína , Estrutura Secundária de Proteína , Transdução de Sinais , Proteína Wnt3A/química , Xenopus
7.
J Immunol ; 188(2): 832-43, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22174454

RESUMO

Respiratory viral infections have been associated with an increased incidence of allergic asthma. However, the mechanisms by which respiratory infections facilitate allergic airway disease are incompletely understood. We previously showed that exposure to a low dose of house dust mite (HDM) resulted in enhanced HDM-mediated allergic airway inflammation, and, importantly, marked airway hyperreactivity only when allergen exposure occurred during an acute influenza A infection. In this study, we evaluated the impact of concurrent influenza infection and allergen exposure at the genomic level, using whole-genome microarray. Our data showed that, in contrast to exposure to a low dose of HDM, influenza A infection led to a dramatic increase in gene expression, particularly of TLRs, C-type lectin receptors, several complement components, as well as FcεR1. Additionally, we observed increased expression of a number of genes encoding chemokines and cytokines associated with the recruitment of proinflammatory cells. Moreover, HDM exposure in the context of an influenza A infection resulted in the induction of unique genes, including calgranulin A (S100a8), an endogenous damage-associated molecular pattern and TLR4 agonist. In addition, we observed significantly increased expression of serum amyloid A (Saa3) and serine protease inhibitor 3n (Serpina3n). This study showed that influenza infection markedly increased the expression of multiple gene classes capable of sensing allergens and amplifying the ensuing immune-inflammatory response. We propose that influenza A infection primes the lung environment in such a way as to lower the threshold of allergen responsiveness, thus facilitating the emergence of a clinically significant allergic phenotype.


Assuntos
Genoma Viral/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Análise de Componente Principal/métodos , Pyroglyphidae/genética , Pyroglyphidae/imunologia , Alérgenos/administração & dosagem , Alérgenos/imunologia , Animais , Feminino , Regulação Viral da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Análise de Sequência com Séries de Oligonucleotídeos , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Pyroglyphidae/virologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia , Hipersensibilidade Respiratória/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Fatores de Tempo
8.
J Allergy Clin Immunol ; 131(1): 187-200.e1-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23006545

RESUMO

BACKGROUND: Allergen exposure at lung and gut mucosae can lead to aberrant T(H)2 immunity and allergic disease. The epithelium-associated cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 are suggested to be important for the initiation of these responses. OBJECTIVE: We sought to investigate the contributions of TSLP, IL-25, and IL-33 in the development of allergic disease to the common allergens house dust mite (HDM) or peanut. METHODS: Neutralizing antibodies or mice deficient in TSLP, IL-25, or IL-33 signaling were exposed to HDM intranasally or peanut intragastrically, and immune inflammatory and physiologic responses were evaluated. In vitro assays were performed to examine specific dendritic cell (DC) functions. RESULTS: We showed that experimental HDM-induced allergic asthma and food allergy and anaphylaxis to peanut were associated with TSLP production but developed independently of TSLP, likely because these allergens functionally mimicked TSLP inhibition of IL-12 production and induction of OX40 ligand (OX40L) on DCs. Blockade of OX40L significantly lessened allergic responses to HDM or peanut. Although IL-25 and IL-33 induced OX40L on DCs in vitro, only IL-33 signaling was necessary for intact allergic immunity, likely because of its superior ability to induce DC OX40L and expand innate lymphoid cells in vivo. CONCLUSION: These data identify a nonredundant, IL-33-driven mechanism initiating T(H)2 responses to the clinically relevant allergens HDM and peanut. Our findings, along with those in infectious and transgenic/surrogate allergen systems, favor a paradigm whereby multiple molecular pathways can initiate T(H)2 immunity, which has implications for the conceptualization and manipulation of these responses in health and disease.


Assuntos
Alérgenos/imunologia , Arachis/imunologia , Hipersensibilidade/imunologia , Interleucinas/imunologia , Pyroglyphidae/imunologia , Timo/imunologia , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Trato Gastrointestinal/imunologia , Humanos , Hipersensibilidade/metabolismo , Interleucina-33 , Interleucina-4/imunologia , Interleucina-4/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Ligante OX40/imunologia , Ligante OX40/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Células Estromais/imunologia , Células Estromais/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Timo/citologia
9.
J Immunol ; 187(7): 3603-12, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-21873529

RESUMO

Production of pathogenic Abs contributes to disease progression in many autoimmune disorders. The immunosuppressant agent mycophenolic acid (MPA) has shown clinical efficacy for patients with autoimmunity. The goal of these studies was to elucidate the mechanisms of action of MPA on B cells isolated from healthy individuals and autoimmune patients. In this study, we show that MPA significantly inhibited both proliferation and differentiation of primary human B cells stimulated under various conditions. Importantly, MPA did not globally suppress B cell responsiveness or simply induce cell death, but rather selectively inhibited early activation events and arrested cells in the G0/G1 phase of the cell cycle. Furthermore, MPA blocked expansion of both naive and memory B cells and prevented plasma cell (PC) differentiation and Ab production from healthy controls and individuals with rheumatoid arthritis. Finally, whereas MPA potently suppressed Ig secretion from activated primary B cells, terminally differentiated PCs were not susceptible to inhibition by MPA. The target of MPA, IMPDH2, was found to be downregulated in PCs, likely explaining the resistance of these cells to MPA. These results suggest that MPA provides benefit in settings of autoimmunity by directly preventing activation and PC differentiation of B cells; however, MPA is unlikely to impact autoantibody production by preexisting, long-lived PCs.


Assuntos
Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Separação Celular , Técnicas de Cocultura , Citometria de Fluxo , Humanos , Ativação Linfocitária/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia
10.
Am J Respir Crit Care Med ; 185(7): 715-22, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22281830

RESUMO

RATIONALE: Bronchial remodeling, including increased bronchial smooth muscle (BSM) mass, contributes to bronchial obstruction in asthma. However, its mechanisms are complex and remain controversial. Recently, a role of the chitinase 3-like 1 protein (YKL-40) has been evoked in asthma. Indeed, YKL-40 concentration was increased in asthmatic serum, and correlated with asthma severity and subepithelial membrane thickness. Nevertheless, the role of YKL-40 on BSM cells remains to be investigated. OBJECTIVES: To evaluate whether YKL-40 altered the physiologic properties of BSM cells in asthma in vitro and ex vivo. METHODS: We enrolled 40 subjects with asthma, 13 nonsmokers, and 16 smokers. BSM cells were derived from bronchial specimens obtained by either fiberoptic bronchoscopy or lobectomy. We assessed cell proliferation using BrdU, flow cytometry, and cell count; signaling intermediates using Western blot; cell migration using inserts, wound healing, and phalloidin staining; and cell synthesis using ELISA and Western blot. The involvement of protease activated receptor (PAR)-2 was evaluated using blocking antibody and dedicated lentiviral small hairpin RNA. We also determined the BSM area and the YKL-40 staining ex vivo using immunohistochemistry on biopsies from subjects with asthma and control subjects. MEASUREMENTS AND MAIN RESULTS: We demonstrated that YKL-40 increased BSM cell proliferation and migration through PAR-2-, AKT-, ERK-, and p38-dependent mechanisms. The increased cell migration was higher in BSM cells of subjects with asthma than that of control subjects. Furthermore, YKL-40 epithelial expression was positively correlated with BSM mass in asthma. CONCLUSIONS: This study indicates that YKL-40 promotes BSM cell proliferation and migration through a PAR-2-dependent mechanism.


Assuntos
Adipocinas/fisiologia , Remodelação das Vias Aéreas/fisiologia , Asma/fisiopatologia , Brônquios/fisiopatologia , Lectinas/fisiologia , Músculo Liso/fisiopatologia , Adipocinas/sangue , Adolescente , Adulto , Idoso , Apoptose/fisiologia , Asma/sangue , Western Blotting , Brônquios/citologia , Contagem de Células , Movimento Celular/fisiologia , Proliferação de Células , Células Cultivadas , Proteína 1 Semelhante à Quitinase-3 , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Lectinas/sangue , Masculino , Pessoa de Meia-Idade , Músculo Liso/citologia , Receptor PAR-2/fisiologia , Transdução de Sinais/fisiologia , Adulto Jovem
11.
J Infect Dis ; 205(8): 1311-20, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22262795

RESUMO

Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager(-/-)) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflammatory cytokines, and a reduction in viral load. To assess the contribution of soluble RAGE (sRAGE) to RSV-induced disease, wild-type and ager(-/-) mice were given doses of sRAGE following RSV infection. Of interest, sRAGE treatment prevented RSV-induced weight loss and neutrophilic inflammation to a degree similar to that observed in ager(-/-) mice. Our work further elucidates the roles of RAGE in the pathogenesis of respiratory infections and highlights the opposing roles of membrane and sRAGE in modulating the host response to RSV infection.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Receptores Imunológicos/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Animais , Pulmão/metabolismo , Camundongos , Camundongos Knockout , Nariz , Isoformas de Proteínas , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Carga Viral
12.
J Immunother Cancer ; 11(3)2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36990508

RESUMO

BACKGROUND: High-risk human papillomavirus (HPV) is a primary cause of an increasing number of oropharyngeal squamous cell carcinomas (OPSCCs). The viral etiology of these cancers provides the opportunity for antigen-directed therapies that are restricted in scope compared with cancers without viral components. However, specific virally-encoded epitopes and their corresponding immune responses are not fully defined. METHODS: To understand the OPSCC immune landscape, we conducted a comprehensive single-cell analysis of HPV16+ and HPV33+ primary tumors and metastatic lymph nodes. We used single-cell analysis with encoded peptide-human leukocyte antigen (HLA) tetramers to analyze HPV16+ and HPV33+ OPSCC tumors, characterizing the ex vivo cellular responses to HPV-derived antigens presented in major Class I and Class II HLA alleles. RESULTS: We identified robust cytotoxic T-cell responses to HPV16 proteins E1 and E2 that were shared across multiple patients, particularly in HLA-A*01:01 and HLA-B*08:01. Responses to E2 were associated with loss of E2 expression in at least one tumor, indicating the functional capacity of these E2-recognizing T cells and many of these interactions validated in a functional assay. Conversely, cellular responses to E6 and E7 were limited in quantity and cytotoxic capacity, and tumor E6 and E7 expression persisted. CONCLUSIONS: These data highlight antigenicity beyond HPV16 E6 and E7 and nominate candidates for antigen-directed therapies.


Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Papillomavirus Humano 16 , Microambiente Tumoral
13.
J Exp Med ; 203(6): 1407-12, 2006 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-16717117

RESUMO

Caspase-1 is activated by a variety of stimuli after the assembly of the "inflammasome," an activating platform made up of a complex of the NOD-LRR family of proteins. Caspase-1 is required for the secretion of proinflammatory cytokines, such as interleukin (IL)-1beta and IL-18, and is involved in the control of many bacterial infections. Paradoxically, however, its absence has been reported to confer resistance to oral infection by Salmonella typhimurium. We show here that absence of caspase-1 or components of the inflammasome does not result in resistance to oral infection by S. typhimurium, but rather, leads to increased susceptibility to infection.


Assuntos
Caspase 1/metabolismo , Inflamação/microbiologia , Salmonella typhimurium/enzimologia , Salmonella typhimurium/patogenicidade , Animais , Caspase 1/deficiência , Caspase 1/genética , Colite/genética , Colite/microbiologia , Primers do DNA , Suscetibilidade a Doenças , Genoma , Inflamação/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Infecções por Salmonella/genética , Estreptomicina/farmacologia
14.
Eur J Immunol ; 41(4): 952-62, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21360526

RESUMO

IL-9 is a pleiotropic cytokine with key functions in tolerance and inflammation, and its expression is considered a hallmark of Th2-lineage cells. Here, we report that human and mouse Th17 cells are a significant source of IL-9. The expression of IL-9 by Th17 cells was strictly dependent on the presence of TGF-ß and IL-1ß, and inhibited by IL-4. IL-9-deficient Th17 cells induced more severe autoimmune gastritis following transfer to nu/nu recipient mice. Th17 cells did not appear to be the target of IL-9 bioactivity as Th17 expansion and differentiation was comparable using IL-9-deficient CD4(+) cells or when IL-9 was neutralized with antibodies in vitro. However, reduced mast cell activity was associated with the increased pathogenicity of IL-9-deficient Th17 cells. Together, these results demonstrate a previously unappreciated role for IL-9 in dampening the pathogenic activities of Th17 cells.


Assuntos
Doenças Autoimunes/imunologia , Gastrite/imunologia , Interleucina-9/imunologia , Células Th17/imunologia , Animais , Comunicação Autócrina , Doenças Autoimunes/patologia , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Gastrite/patologia , Humanos , Memória Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Especificidade de Órgãos , Células Th17/citologia
15.
Ann Rheum Dis ; 71(8): 1402-10, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22730375

RESUMO

BACKGROUND: Angiopoietin (Ang)-1 and Ang-2, and their shared receptor Tie2, are expressed in rheumatoid arthritis (RA) synovial tissue, but the cellular targets of Ang signalling and the relative contributions of Ang-1 and Ang-2 to arthritis are poorly understood. OBJECTIVES: To determine the cellular targets of Ang signalling in RA synovial tissue, and the effects of Ang-2 neutralisation in murine collagen-induced arthritis (CIA). METHODS: RA and psoriatic arthritis (PsA) synovial biopsies were examined for expression of Tie2 and activated phospho (p)-Tie2 by quantitative immunohistochemistry and immunofluorescent double staining. Human monocyte and macrophage Tie2 expression was determined by flow cytometry and quantitative PCR. Regulation of macrophage intracellular signalling pathways and gene expression were examined by immunoblotting and ELISA. CIA was assessed in mice treated with saline, control antibody, prednisolone or neutralising anti-Ang-2 antibody. RESULTS: Expression of synovial Tie2 and p-Tie2 was similar in RA and PsA. Tie2 activation in RA patient synovial tissue was predominantly localised in synovial macrophages and was expressed by human macrophage. Ang-1 and Ang-2 stimulated activation of multiple intracellular signalling pathways, and cooperated with tumour necrosis factor to induce macrophage interleukin 6 and macrophage inflammatory protein 1α production. Ang-2 selectively suppressed macrophage thrombospondin-2 production. Ang-2 neutralisation significantly decreased disease severity, synovial inflammation, neo-vascularisation and joint destruction in established CIA. CONCLUSIONS: The authors identify synovial macrophages as primary targets of Ang signalling in RA, and demonstrate that Ang-2 promotes the pro-inflammatory activation of human macrophages. Ang-2 makes requisite contributions to pathology in CIA, indicating that targeting Ang-2 may be of therapeutic benefit in the treatment of RA.


Assuntos
Angiopoietina-2/farmacologia , Artrite Experimental/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/genética , Angiopoietina-1/metabolismo , Angiopoietina-1/farmacologia , Angiopoietina-2/imunologia , Angiopoietina-2/metabolismo , Animais , Anticorpos Bloqueadores/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Psoriásica/metabolismo , Artrite Psoriásica/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Quimiocina CCL3/biossíntese , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/biossíntese , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Fosforilação , Receptores Proteína Tirosina Quinases/metabolismo , Receptor TIE-2 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Trombospondinas/biossíntese
16.
J Immunol ; 184(3): 1168-79, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20042593

RESUMO

Human metapneumoviruses (HMPVs) are recently identified Paramyxoviridae that contribute to respiratory tract infections in children. No effective treatments or vaccines are available. Successful defense against virus infection relies on early detection by germ line-encoded pattern recognition receptors and activation of cytokine and type I IFN genes. Recently, the RNA helicase retinoic acid-inducible gene I (RIG-I) has been shown to sense HMPV. In this study, we investigated the abilities of two prototype strains of HMPV (A1 [NL\1\00] and B1 [NL\1\99]) to activate RIG-I and induce type I IFNs. Despite the abilities of both HMPV-A1 and HMPV-B1 to infect and replicate in cell lines and primary cells, only the HMPV-A1 strain triggered RIG-I to induce IFNA/B gene transcription. The failure of the HMPV-B1 strain to elicit type I IFN production was dependent on the B1 phosphoprotein, which specifically prevented RIG-I-mediated sensing of HMPV viral 5' triphosphate RNA. In contrast to most cell types, plasmacytoid dendritic cells displayed a unique ability to sense both HMPV-A1 and HMPV-B1 and in this case sensing was via TLR7 rather than RIG-I. Collectively, these data reveal differential mechanisms of sensing for two closely related viruses, which operate in cell type-specific manners.


Assuntos
RNA Helicases DEAD-box/metabolismo , Metapneumovirus/imunologia , Fosfoproteínas/metabolismo , Receptor 7 Toll-Like/metabolismo , Interferência Viral/imunologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Proteína DEAD-box 58 , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/fisiologia , Regulação Viral da Expressão Gênica/imunologia , Humanos , Imunidade Inata , Interferon-alfa/biossíntese , Interferon-alfa/genética , Interferon beta/biossíntese , Interferon beta/genética , Ligantes , Metapneumovirus/genética , Metapneumovirus/patogenicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Paramyxoviridae/imunologia , Infecções por Paramyxoviridae/metabolismo , Infecções por Paramyxoviridae/virologia , Fosfoproteínas/genética , RNA Viral/genética , Receptores Imunológicos , Especificidade da Espécie , Receptor 7 Toll-Like/deficiência , Receptor 7 Toll-Like/fisiologia , Células Vero
17.
Nature ; 442(7106): 997-1002, 2006 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-16921386

RESUMO

Contrary to the proinflammatory role of mast cells in allergic disorders, the results obtained in this study establish that mast cells are essential in CD4+CD25+Foxp3+ regulatory T (T(Reg))-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of T(Reg) cells, acquire a unique genetic signature dominated by the expression of mast-cell-gene products. We also show that mast cells are crucial for allograft tolerance, through the inability to induce tolerance in mast-cell-deficient mice. High levels of interleukin (IL)-9--a mast cell growth and activation factor--are produced by activated T(Reg) cells, and IL-9 production seems important in mast cell recruitment to, and activation in, tolerant tissue. Our data indicate that IL-9 represents the functional link through which activated T(Reg) cells recruit and activate mast cells to mediate regional immune suppression, because neutralization of IL-9 greatly accelerates allograft rejection in tolerant mice. Finally, immunohistochemical analysis clearly demonstrates the existence of this novel T(Reg)-IL-9-mast cell relationship within tolerant allografts.


Assuntos
Tolerância Imunológica/imunologia , Mastócitos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Contagem de Células , Regulação da Expressão Gênica/genética , Rejeição de Enxerto/imunologia , Interleucina-9/imunologia , Interleucina-9/metabolismo , Mastócitos/citologia , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos , Pele/citologia , Pele/imunologia , Transplante de Pele/imunologia , Fatores de Tempo , Transplante Homólogo/imunologia
18.
Am J Respir Crit Care Med ; 183(2): 179-88, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20732990

RESUMO

RATIONALE: Current thinking accredits eosinophils with preeminent contributions to allergic airway responses, including a major role in the development of airway remodeling, a process thought to significantly contribute to airway dysfunction. However, direct evidence in support of this notion is limited and often controversial. OBJECTIVES: We elucidated the requirement for eosinophils in the generation of allergic sensitization, airway inflammation, and remodeling in a model involving chronic respiratory exposure to house dust mite (HDM). METHODS: We used three methods to selectively eliminate eosinophils, a depleting antibody (anti-CCR3), and two strains of eosinophil-deficient mice (ΔdblGATA and the transgenic line PHIL). MEASUREMENTS AND MAIN RESULTS: Anti-CCR3 treatment markedly reduced pulmonary eosinophilia (> 80%) over the course of HDM exposure but had no effect on the remaining inflammatory response, the extent of lung Th2 cells, or the development of remodeling-associated changes, including subepithelial collagen deposition and smooth muscle thickening. In addition, we observed that, despite the absence of eosinophils, HDM-exposed GATA mice mounted robust airway and lung inflammation and hyperresponsiveness and showed a remodeling response equivalent to that observed in wild-type mice. Moreover, these mice had similar serum HDM-specific IgE levels and Th2-associated splenocyte cytokine production as HDM-exposed wild-type control mice. Similar observations were made in PHIL eosinophil-deficient mice subjected to chronic HDM exposure, although slight decreases in airway mononuclear cells, but not lung Th2 cells, and remodeling were noted. CONCLUSIONS: Collectively, these data demonstrate that, at variance with the prevailing paradigm, eosinophils play negligible roles in the generation of HDM-induced allergic immunity and airway remodeling.


Assuntos
Eosinófilos/imunologia , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Colágeno/imunologia , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Inflamação/etiologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo
19.
Am J Respir Crit Care Med ; 183(7): 865-75, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20971830

RESUMO

RATIONALE: IL-9 is a pleiotropic cytokine that has multiple effects on structural as well as numerous hematopoietic cells, which are central to the pathogenesis of asthma. OBJECTIVES: The contribution of IL-9 to asthma pathogenesis has thus far been unclear, due to conflicting reports in the literature. These earlier studies focused on the role of IL-9 in acute inflammatory models; here we have investigated the effects of IL-9 blockade during chronic allergic inflammation. METHODS: Mice were exposed to either prolonged ovalbumin or house dust mite allergen challenge to induce chronic inflammation and airway remodeling. MEASUREMENTS AND MAIN RESULTS: We found that IL-9 governs allergen-induced mast cell (MC) numbers in the lung and has pronounced effects on chronic allergic inflammation. Anti-IL-9 antibody-treated mice were protected from airway remodeling with a concomitant reduction in mature MC numbers and activation, in addition to decreased expression of the profibrotic mediators transforming growth factor-ß1, vascular endothelial growth factor, and fibroblast growth factor-2 in the lung. Airway remodeling was associated with impaired lung function in the peripheral airways and this was reversed by IL-9 neutralization. In human asthmatic lung tissue, we identified MCs as the main IL-9 receptor expressing population and found them to be sources of vascular endothelial growth factor and fibroblast growth factor-2. CONCLUSIONS: Our data suggest an important role for an IL-9-MC axis in the pathology associated with chronic asthma and demonstrate that an impact on this axis could lead to a reduction in chronic inflammation and improved lung function in patients with asthma.


Assuntos
Alérgenos/imunologia , Asma/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Interleucina-9/imunologia , Pulmão/imunologia , Pulmão/patologia , Mastócitos/imunologia , Alérgenos/administração & dosagem , Análise de Variância , Animais , Asma/metabolismo , Biomarcadores/metabolismo , Biópsia por Agulha , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/farmacologia , RNA Mensageiro/análise , Distribuição Aleatória , Testes de Função Respiratória , Estatísticas não Paramétricas
20.
J Allergy Clin Immunol ; 127(6): 1552-61.e1, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21624619

RESUMO

BACKGROUND: Food-induced anaphylaxis is often a severe allergic reaction characterized by multiorgan dysfunction and a potentially fatal outcome. OBJECTIVES: We sought to investigate the relative contribution of immunoglobulin-dependent effector pathways to anaphylactic responses to food (ie, peanut). METHODS: Wild-type and various mutant mice were sensitized with peanut protein and cholera toxin by means of oral gavage weekly for 4 weeks. Mice were subjected to different cellular depletion and Fc receptor blocking strategies before challenge with peanut 1 week after the last sensitization. RESULTS: Our data indicate that pathways other than the classical mast cell (MC)-IgE pathway contribute to the full spectrum of anaphylactic reactions to peanut. We show that the single deletion of MCs, basophils, or phagocytes (ie, macrophages) prevents the most significant clinical outcome: death. Remarkably, the combined deficiency of MCs and phagocytes, but not MCs and basophils, averted nearly all clinical and physiological signs of anaphylaxis. Furthermore, blockade of both IgE and IgG1 signaling was necessary to abolish anaphylactic responses to peanut. Although MC responses occurred through IgE and IgG1, phagocyte responses were fully mediated through IgG1. CONCLUSIONS: Peanut-induced anaphylaxis is a process that involves the concerted action of multiple immune effector pathways, and thus interventions targeting a single pathway (eg, MC-IgE) might not be sufficient to fully prevent anaphylactic responses.


Assuntos
Anafilaxia/imunologia , Hipersensibilidade a Amendoim/imunologia , Anafilaxia/etiologia , Anafilaxia/prevenção & controle , Animais , Basófilos/imunologia , Feminino , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Macrófagos/imunologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Hipersensibilidade a Amendoim/etiologia , Receptores de IgG/metabolismo , Transdução de Sinais/imunologia
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