IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice

Background<p></p> The initiation and regulation of pulmonary fibrosis are not well understood. IL-33, an important cytokine for respiratory diseases, is overexpressed in the lungs of patients with idiopathic pulmonary fibrosis.<p></p> Objectives<p></p> We aimed to determine the effects and mechanism of IL-33 on the development and severity of pulmonary fibrosis in murine bleomycin-induced fibrosis.<p></p> Methods<p></p> Lung fibrosis was induced by bleomycin in wild-type or Il33r (St2)−/− C57BL/6 mice treated with the recombinant mature form of IL-33 or anti–IL-33 antibody or transferred with type 2 innate lymphoid cells (ILC2s). The development and severity of fibrosis was evaluated based on lung histology, collagen levels, and lavage cytology. Cytokine and chemokine levels were quantified by using quantitative PCR, ELISA, and cytometry.<p></p> Results<p></p> IL-33 is constitutively expressed in lung epithelial cells but is induced in macrophages by bleomycin. Bleomycin enhanced the production of the mature but reduced full-length form of IL-33 in lung tissue. ST2 deficiency, anti–IL-33 antibody treatment, or alveolar macrophage depletion attenuated and exogenous IL-33 or adoptive transfer of ILC2s enhanced bleomycin-induced lung inflammation and fibrosis. These pathologic changes were accompanied, respectively, by reduced or increased IL-33, IL-13, TGF-β1, and inflammatory chemokine production in the lung. Furthermore, IL-33 polarized M2 macrophages to produce IL-13 and TGF-β1 and induced the expansion of ILC2s to produce IL-13 in vitro and in vivo.<p></p> Conclusions<p></p> IL-33 is a novel profibrogenic cytokine that signals through ST2 to promote the initiation and progression of pulmonary fibrosis by recruiting and directing inflammatory cell function and enhancing profibrogenic cytokine production in an ST2- and macrophage-dependent manner

Imunopatologia da dengue: receptores de quimiocinas CC e células iNKT

Exportado OPUSMade available in DSpace on 2019-08-14T04:34:34Z (GMT). No. of bitstreams: 1 pdf___tese_rodrigo_guabiraba_brito___2010.pdf: 20716853 bytes, checksum: 845682a9cb9ce2becf2c15b6c6a7a9e4 (MD5) Previous issue date: 6O Dengue virus (DENV), um flavivirus transmitido por mosquitos, é um sério problema de saude publica em paises tropicais. Mecanismos da resposta imune na infeccao ainda nao estao bem elucidados. Dados clinicos tem mostrado uma associacao entre niveis de quimiocinas CC no plasma e a severidade da doenca. Neste contexto, avaliamos o papel de receptores de quimiocinas CC, CCR1, CCR2 e CCR4, na infeccao pelo dengue utilizando animais KO para estes receptores. Alemdisso, avaliamos in vivo a contribuicao de celulas NKT invariantes (iNKT), linfocitos T ¿À nao convencionais, na resposta do hospedeiro utili zando uma amostra de DENV-2 adaptada em camundongos que leva a uma infeccao que se assemelha ao quadro de FHD/SCD. Camundongos C57/Bl6 (WT) apresentam sinais clinicos e danotecidual, incluindo trombocitopenia, hemoconcentracao, niveis elevados de transaminases e citocinas pro-inflamatorias, alem de mortalidade. Quimiocinas CC, como CCL2, CCL3 e CCL5, sao produzidas no baco e figado de animais WT. Animais CCR1-/- possuem fenotipo moderado, com doenca e mortalidade similares a animais WT. Em animais CCR2-/- a mortalidade, dano hepatico, niveis de IL-6 e IFN-Á, e ativacao de leucocitos foram atenuadas. Entretanto, trombocitopenia,hemoconcentracao e niveis sistemicos de TNF- ¿ foram similares aos de animais WT. CCL17, um ligante de CCR4, e produzido durante a infeccao. Em animais CCR4-/- a mortalidade, lesao tecidual e inflamacao sistemi ca estao fortemente reduzidas. Mesmo com diferencas no perfil de doencaem animais KO, nao houve alteracoes na carga viral. Celulas iNKT esplenicas e hepaticas sao ativadas e produzem IFN-Á na infeccao. Animais deficientes em iNKT (J¿18-/-) sao bastante resistentes a infeccao, comparados a animais WT. Este fenotipo e parcialmente revertido pela transferencia de celulas iNKT purifi cadas para animais J¿18-/-. Estes animais apresentam resposta inflamatoria reduzida, com baixos niveis de IL-6, IFN-Á e CXCL1, reduzida lesao hepatica e menor ativacao d e celulas NK eneutrofilos. A carga viral no baco e figado tambem foi reduzida. Tratamento com ¿GalCer e a delecao de CD1d nao alteram o fenotipo observado em animais WT. Em resumo, receptores de quimiocinas CC tem papeis diferentes na infeccao pelo DENV-2 e a ativacao endogena de celulas iNKT durante a infeccao contribui de forma importante para a resposta sistemica e local associada a sindr ome do choque pelo dengue em camundongos.Dengue virus (DENV), a mosquito-borne flavivirus, is a serious public health problem in many tropical countries. Immune mechanisms involved in the pathogenesis of DENV infection are not fully elucidated. Recent clinical data showed an association between levels of different CC chemokines in plasma and severity of dengue. In this regard, we evaluated the role of CC chemokine receptors CCR1, CCR2 and CCR4 in dengue infection using KO mice for these receptors. Furthermore, we assessed the in vivo contribution of invariant Natural Killer T (iNKT)cells, non-conventional áâ T lymphocytes, to the host response using a mouseadapted DENV-2 strain that causes a disease resembling severe dengue infection. Infected C57/Bl6 mice (WT) presented clinical disease and tissue damage, including thrombocytopenia, hemoconcentration, increased levels of transaminases and proinflammatory cytokines, and lethality. CC chemokines, such as CCL2, CCL3 and CCL5, are strongly produced in spleen and liver of WT mice. CCR1-/- mice had a mildphenotype with disease presentation and lethality similar to those of WT mice. In CCR2-/- mice, lethality, liver damage, levels of IL-6 and IFN-ã, and leukocyte activation were attenuated. However, thrombocytopenia, hemoconcentration and systemic TNF-á levels were similar to infected WT mice. CCL17, a CCR4 ligand, is produced upon infection. In CCR4-/- mice, lethality, tissue injury and systemic inflammation were markedly decreased. Despite differences in disease presentation in CCR-deficient mice, there were no significant differences in viral load. Splenic andhepatic iNKT cells became activated and produce IFN-ã upon infection. Mice deficient in iNKT cells (Já18-/-) are highly resistant to the infection when compared to WT animals. The phenotype was partially recovered by adoptive transfer of iNKT cells to Já18-/-animals. Já18-/- mice presented decreased systemic and local inflammatory responses, with lower levels of IL-6, IFN-ã and CXCL1, reduced liver injury and diminished activation of NK cells and neutrophils. Viral load in spleen and liver was also lower in Já18-/- mice relative to WT mice. áGalCer treatment and CD1dablation had no effects in disease progression. In conclusion, CC chemokine receptors have discrete roles in DENV-2 and endogenous iNKT cell activation during DV infection contributes to the systemic and local inflammatory responses that lead to shock and death, suggesting that CC chemokine receptors and iNKT cells may be associated to the inflammatory response involved in dengue shock syndrome in mice

Papel dos receptores canabinóides em um modelo experimental de angiogênese inflamatória

Exportado OPUSMade available in DSpace on 2019-08-14T18:44:25Z (GMT). No. of bitstreams: 1 mestrado_final_completo_rodrigo_guabiraba_brito_2007.pdf: 1687282 bytes, checksum: ab0d1991e70e6d0cc1976cd531b2403b (MD5) Previous issue date: 27A angiogênese é controlada por uma complexa rede de células e mediadores. A ativação ou bloqueio de receptores canabinóides demonstram ser uma interessante estratégia farmacológica para atenuar a resposta angiogênica e/ou inflamatória em vários modelos experimentais. Aqui investigamos como esta estratégia pode interferir na angiogênese inflamatória. Esponjas de polyester-poliuretana foram implantadas em camundongos C57BL/6. Os animais receberam doses diárias (10 mg/Kg, s.c.) dos antagonistas canabinóides SR141716A (CB1) and SR144528 (CB2), separadamente, ou 3 e 10 mg/Kg (30 ou 100 g/animal, para o tratamento local) (s.c.) do agonista CB1/CB2 WIN 55,212-2, por 7 ou 14 dias. Os implantes foram coletados para análises por ELISA, hemoglobina, mieloperoxidase e N-acetilglicosaminidase, utilizadas, respectivamente, como index para mediadores protéicos, angiogênese e acúmulo de neutrófilos e macrófagos, respectivamente. O tratamento com os antagonistas CB1 ou CB2 levou à redução do influxo celular para a matriz esponjosa nos dias 7 e 14, com padrões distintos para macrófagos e neutrófilos. O agonista CB1/CB2 também reduziu o influxo celular. Ambos os tratamentos interferiram na angiogênese. Estas alterações foram acompanhadas por mudanças nos níveis de TNF-, VEGF, CXCL1-3/KC, CCL2/JE e RANTES, dependendo do tratamento. Todas as mudanças apresentam padrões similares na análise histológica. A ativação ou bloqueio de receptores canabinóides parece ser efetivo em reduzir as respostas angiogênica e inflamatória. Embora agindo de forma similar, níveis de citocinas, quimiocinas e endocanabinóides podem explicar esta resposta paradoxal. Desensibilização dos receptores e atividade agonista parcial / agonista inverso são outras explicações plausíveis para estas respostas.Angiogenesis depends on a complex network of cells and mediators. The activation or blockade of cannabinoid receptors showed to be an interesting pharmacological strategy to attenuate the angiogenic and/or inflammatory response in many experimental models. Here we investigated how this strategy may interfere in inflammatory angiogenesis. Polyester-polyurethane sponges were implanted in C57BL/6 mice. Animals received daily doses (10 mg/kg, s.c.) of the cannabinoid antagonists SR141716A (CB1) and SR144528 (CB2), separately, or 3 and 10 mg/Kg (30 or 100 ìg/mice, for the local treatment) (s.c.) of the cannabinoid CB1/CB2 agonist WIN 55212-2, for 7 or 14 days. The implants were then collected for ELISA, hemoglobin, myeloperoxidase and N-acetylglucosaminidase measurements, used as indexes for angiogenesis, neutrophil and macrophage accumulation, respectively. Histological analysis was also conducted. CB1 or CB2 receptor antagonist treatment was able to reduce cellular influx to the sponge at 7 and 14 days, with distinctive pattern for macrophages and neutrophils. The CB1/CB2 agonist also reduced cellular influx. Both treatments affected angiogenesis. These alterations were accompanied by changes in the levels of TNF-á, VEGF, CXCL1-3/KC, CCL2/JE and RANTES, depending on the treatment. All changes correspond to a similar pattern in the histological analysis. The blockade or activation of cannabinoid receptors showed to be effective in reducing inflammatory and angiogenic responses. Altough acting in a similar way, levels of cytokines, chemokines and endocannabinoids may help explain this paradoxal response. Partial agonism / inverse agonism activity and receptor desensitization is another explanation for these responses.Keywords: angiogenesis, inflammation, cannabinoid receptors, cytokine

Avian colibacillosis: still many black holes

Avian pathogenic Escherichia coli (APEC) strains cause severe respiratory and systemic disease, threatening food security and avian welfare worldwide. Intensification of poultry production and the quick expansion of free-range production systems will increase the incidence of colibacillosis through greater exposure of birds to pathogens and stress. Therapy is mainly based on antibiotherapy and current vaccines have poor efficacy. Serotyping remains the most frequently used diagnostic method, only allowing the identification of a limited number of APEC strains. Several studies have demonstrated that the most common virulence factors studied in APEC are rarely all present in the same isolate, showing that APEC strains constitute a heterogeneous group. Different isolates may harbor different associations of virulence factors, each one able to induce colibacillosis. Despite its economical relevance, pathogenesis of colibacillosis is poorly understood. Our knowledge on the host response to APEC is based in very descriptive studies, mostly restricted to bacteriological and histopathological analysis of infected organs, mostly lungs. Furthermore, only a small number of APEC isolates has been used in experimental studies. In the present review we discuss current knowledge on APEC diversity and virulence, including host-response to infection and the associated inflammatory response with a focus on pulmonary colibacillosis

Exploring the Homeostatic and Sensory Roles of the Immune System

Immunology developed under the notion of the immune system exists to fight pathogens. Recently, the discovery of interactions with commensal microbiota that are essential to human health initiated a change in this old paradigm. Here, we argue that the immune system has major physiological roles extending far beyond defending the host. Immune and inflammatory responses share the core property of sensing, defining the immune system also as a sensory system. The inference with the immune system collects, interprets, and stores information, while creating an identity of self, places it in close relationship to the nervous system, which suggests that these systems may have a profound evolutionary connection

Dynamics of structural barriers and innate immune components during incubation of the avian egg : critical interplay between autonomous embryonic development and maternal anticipation

The integrated innate immune features of the calcareous egg and its contents are a critical underpinning of the remarkable evolutionary success of the Aves clade. Beginning at the time of laying, the initial protective structures of the egg, i.e., the biomineralized eggshell, egg-white antimicrobial peptides, and vitelline membrane, are rapidly and dramatically altered during embryonic development. The embryo-generated extra-embryonic tissues (chorioallantoic/amniotic membranes, yolk sac, and associated chambers) are all critical to counteract degradation of primary egg defenses during development. With a focus on the chick embryo (Gallus gallus domesticus), this review describes the progressive transformation of egg innate immunity by embryo-generated structures and mechanisms over the 21-day course of egg incubation, and also discusses the critical interplay between autonomous development and maternal anticipation

Evolution of innate immunity components during incubation of the avian egg

National audienc

Dynamics of structural barriers and innate immune components during incubation of the avian egg : critical interplay between autonomous embryonic development and maternal anticipation

Article en Open AccessInternational audienceThe integrated innate immune features of the calcareous egg and its contents are a critical underpinning of the remarkable evolutionary success of the Aves clade. Beginning at the time of laying, the initial protective structures of the egg, i.e., the biomineralized eggshell, egg-white antimicrobial peptides, and vitelline membrane, are rapidly and dramatically altered during embryonic development. The embryo-generated extra-embryonic tissues (chorioallantoic/amniotic membranes, yolk sac, and associated chambers) are all critical to counteract degradation of primary egg defenses during development. With a focus on the chick embryo (Gallus gallus domesticus), this review describes the progressive transformation of egg innate immunity by embryo-generated structures and mechanisms over the 21-day course of egg incubation, and also discusses the critical interplay between autonomous development and maternal anticipation

Complete genome sequences of two Escherichia coli phages vB_EcoM_ ESCO5 and vB_EcoM_ESCO13 which are related to phAPEC8

International audienceWe report here the complete genome sequences of two Myoviridae phages that infect various avian-pathogenic Escherichia coli strains and that are closely related to phage phAPEC8

Unveiling the participation of avian kinin ornithokinin and its receptors in the chicken inflammatory response

International audienceVasoactive peptides are key early mediators of inflammation released through activation of different enzymatic systems. The mammalian kinin-kallikrein (K-KLK) system produces bradykinin (BK) through proteolytic cleavage of a kininogen precursor by enzymes named kallikreins. BK acts through specific ubiquitous G-protein coupled receptors (B1R and B2R) to participate in physiological processes and inflammatory responses, such as activation of mononuclear phagocytes. In chickens, the BK-like nonapeptide omithokinin (OK) has been shown to promote intracellular calcium increase in embryonic fibroblasts and to be vasodilatory in vivo. Also, one of its receptors (B2R) was already cloned. However, the participation of chicken K-KLK system components in the inflammatory response remains unknown and was therefore investigated. We first showed that B1R, B2R and kininogen 1 (KNG1) are expressed in unstimulated chicken tissues and macrophages. We next showed that chicken B1R and B2R are expressed at transcript and protein levels in chicken macrophages and are upregulated by E. coli LPS or avian pathogenic E. coli (APEC) infection. Interestingly, exogenous OK induced internalization and degradation of OK receptors protein, notably B2R. Also, OK induced intracellular calcium increase and potentiated zymosan-induced ROS production and Dextran-FITC endocytosis by chicken macrophages. Exogenous OK itself did not promote APEC killing and had no pro-inflammatory effect. However, when combined with LPS or APEC, OK upregulated cytokine/chemokine gene expression and NO production by chicken macrophages. This effect was not blocked by canonical non-peptide B1R or B2R receptor antagonists but was GPCR- and PI3K/Akt-dependent. In vivo, pulmonary colibacillosis led to upregulation of OK receptors expression in chicken lungs and liver. Also, colibacillosis led to significant upregulation of OK precursor KNG1 expression in liver and in cultured hepatocytes (LMH). We therefore provide hitherto unknown information on how OK and its receptors are involved in inflammation and infection in chickens