RESUMO
Over the past thirty years, the complexity of the αß-T cell compartment has been enriched by the identification of innate-like T cells (ITCs), which are composed mainly of invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. Based on animal studies using ischemia-reperfusion (IR) models, a key role has been attributed to iNKT cells in close connection with the alarmin/cytokine interleukin (IL)-33, as early sensors of cell-stress in the initiation of acute sterile inflammation. Here we have investigated whether the new concept of a biological axis of circulating iNKT cells and IL-33 applies to humans, and may be extended to other ITC subsets, namely MAIT and γδ-T cells, in the acute sterile inflammation sequence occurring during liver transplant (LT). From a prospective biological collection of recipients, we reported that LT was accompanied by an early and preferential activation of iNKT cells, as attested by almost 40% of cells having acquired the expression of CD69 at the end of LT (i.e. 1-3 hours after portal reperfusion), as opposed to only 3-4% of conventional T cells. Early activation of iNKT cells was positively correlated with the systemic release of the alarmin IL-33 at graft reperfusion. Moreover, in a mouse model of hepatic IR, iNKT cells were activated in the periphery (spleen), and recruited in the liver in WT mice, as early as the first hour after reperfusion, whereas this phenomenon was virtually missing in IL-33-deficient mice. Although to a lesser degree than iNKT cells, MAIT and γδ-T cells also seemed targeted during LT, as attested by 30% and 10% of them acquiring CD69 expression, respectively. Like iNKT cells, and in clear contrast to γδ-T cells, activation of MAIT cells during LT was closely associated with both release of IL-33 immediately after graft reperfusion and severity of liver dysfunction occurring during the first three post-operative days. All in all, this study identifies iNKT and MAIT cells in connection with IL-33 as new key cellular factors and mechanisms of acute sterile inflammation in humans. Further investigations are required to confirm the implication of MAIT and iNKT cell subsets, and to precisely assess their functions, in the clinical course of sterile inflammation accompanying LT.
Assuntos
Hepatopatias , Células T Matadoras Naturais , Animais , Humanos , Camundongos , Alarminas/metabolismo , Inflamação/metabolismo , Interleucina-33/metabolismo , Isquemia/metabolismo , Hepatopatias/metabolismo , Células T Matadoras Naturais/metabolismo , Estudos Prospectivos , ReperfusãoRESUMO
Cystic fibrosis is associated with chronic Pseudomonas aeruginosa colonization and inflammation. The role of MyD88, the shared adapter protein of the proinflammatory TLR and IL-1R families, in chronic P. aeruginosa biofilm lung infection is unknown. We report that chronic lung infection with the clinical P. aeruginosa RP73 strain is associated with uncontrolled lung infection in complete MyD88-deficient mice with epithelial damage, inflammation, and rapid death. Then, we investigated whether alveolar or myeloid cells contribute to heightened sensitivity to infection. Using cell-specific, MyD88-deficient mice, we uncover that the MyD88 pathway in myeloid or alveolar epithelial cells is dispensable, suggesting that other cell types may control the high sensitivity of MyD88-deficient mice. By contrast, IL-1R1-deficient mice control chronic P. aeruginosa RP73 infection and IL-1ß Ab blockade did not reduce host resistance. Therefore, the IL-1R1/MyD88 pathway is not involved, but other IL-1R or TLR family members need to be investigated. Our data strongly suggest that IL-1 targeted neutralizing therapies used to treat inflammatory diseases in patients unlikely reduce host resistance to chronic P. aeruginosa infection.
Assuntos
Interleucina-1beta/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Receptores Tipo I de Interleucina-1/imunologia , Animais , Humanos , Imunidade Inata , Interleucina-1beta/genética , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Infecções por Pseudomonas/metabolismo , Receptores Tipo I de Interleucina-1/genética , Transdução de Sinais , Receptores Toll-Like/imunologiaRESUMO
Innate lymphoid cells (ILCs) are critical mediators of immunological and physiological responses at mucosal barrier sites. Whereas neurotransmitters can stimulate ILCs, the synthesis of small-molecule neurotransmitters by these cells has only recently been appreciated. Group 2 ILCs (ILC2s) are shown here to synthesize and release acetylcholine (ACh) during parasitic nematode infection. The cholinergic phenotype of pulmonary ILC2s was associated with their activation state, could be induced by in vivo exposure to extracts of Alternaria alternata or the alarmin cytokines interleukin-33 (IL-33) and IL-25, and was augmented by IL-2 in vitro. Genetic disruption of ACh synthesis by murine ILC2s resulted in increased parasite burdens, lower numbers of ILC2s, and reduced lung and gut barrier responses to Nippostrongylus brasiliensis infection. These data demonstrate a functional role for ILC2-derived ACh in the expansion of ILC2s for maximal induction of type 2 immunity.
Assuntos
Acetilcolina/biossíntese , Helmintíase/imunologia , Helmintos/imunologia , Imunidade Inata , Imunidade nas Mucosas , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Animais , Biomarcadores , Citocinas/metabolismo , Expressão Gênica , Helmintíase/parasitologia , Interações Hospedeiro-Parasita/imunologia , Imuno-Histoquímica , Imunofenotipagem , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Especificidade de Órgãos/imunologiaAssuntos
Acetilcolina/imunologia , Hiper-Reatividade Brônquica/imunologia , Hipersensibilidade/imunologia , Pulmão/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Papaína/farmacologia , Animais , Hiper-Reatividade Brônquica/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/imunologia , Hipersensibilidade/fisiopatologia , Imunidade Inata , Pulmão/imunologia , Linfócitos/imunologia , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Background: Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder. Methods: Mice with targeted disruption of the molybdenum cofactor sulfurase (Mocos) gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism. Results: Mocos-deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm-Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology. Conclusions: Mocos-deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis.
Assuntos
Nefropatias , Erros Inatos do Metabolismo da Purina-Pirimidina , Urolitíase , Animais , Nefropatias/genética , Camundongos , Erros Inatos do Metabolismo da Purina-Pirimidina/complicações , Urolitíase/genética , Xantina , Xantina DesidrogenaseRESUMO
[This corrects the article DOI: 10.3389/fimmu.2019.00702.].
RESUMO
Cellular response to environmental challenges requires immediate and precise regulation of transcriptional programs. During viral infections, this includes the expression of antiviral genes that are essential to combat the pathogen. Transcribed mRNAs are bound and escorted to the cytoplasm by the cap-binding complex (CBC). We recently identified a protein complex consisting of NCBP1 and NCBP3 that, under physiological conditions, has redundant function to the canonical CBC, consisting of NCBP1 and NCBP2. Here, we provide evidence that NCBP3 is essential to mount a precise and appropriate antiviral response. Ncbp3-deficient cells allow higher virus growth and elicit a reduced antiviral response, a defect happening on post-transcriptional level. Ncbp3-deficient mice suffered from severe lung pathology and increased morbidity after influenza A virus challenge. While NCBP3 appeared to be particularly important during viral infections, it may be more broadly involved to ensure proper protein expression.
Assuntos
Infecções por Orthomyxoviridae/imunologia , Proteínas de Ligação ao Cap de RNA/imunologia , Proteínas de Ligação ao Cap de RNA/metabolismo , Animais , Vírus da Influenza A/imunologia , Camundongos , Camundongos Knockout , Infecções por Orthomyxoviridae/metabolismo , Biossíntese de Proteínas/fisiologiaRESUMO
Maternal immune transfer is the most significant source of protection from early-life infection, but whether maternal transfer of immunity by nursing permanently alters offspring immunity is poorly understood. Here, we identify maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection. Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection. Enhanced control of infection was not dependent on maternal antibody. Protection associated with systemic development of protective type 2 immunity in T helper 2 (TH2) impaired IL-4Rα-/- offspring. This maternally acquired immunity was maintained into maturity and required transfer (via nursing) to the offspring of maternally derived TH2-competent CD4 T cells. Our data therefore reveal that maternal exposure to a globally prevalent source of infection before pregnancy provides long-term nursing-acquired immune benefits to offspring mediated by maternally derived pathogen-experienced lymphocytes.
Assuntos
Animais Lactentes/imunologia , Imunidade Celular , Imunidade Materno-Adquirida , Infecções por Strongylida/imunologia , Animais , Anticorpos Anti-Helmínticos/imunologia , Linfócitos B/imunologia , Linfócitos B/parasitologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Lactação/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nippostrongylus/imunologia , Nippostrongylus/patogenicidade , Gravidez , Receptores de Superfície Celular/genética , Infecções por Strongylida/transmissão , Células Th2/imunologiaRESUMO
Oral T. gondii infection (30 cysts of 76K strain) induces acute lethal ileitis in sensitive C57BL/6 (B6) mice with increased expression of IL-33 and its receptor ST2 in the ileum. Here we show that IL-33 is involved in ileitis, since absence of IL-33R/ST2 attenuated neutrophilic inflammation and Th1 cytokines upon T. gondii infection with enhanced survival. Blockade of ST2 by neutralizing ST2 antibody in B6 mice conferred partial protection, while rmIL-33 aggravated ileitis. Since IL-22 expression further increased in absence of ST2, we blocked IL-22 by neutralizing antibody, which abrogated protection from acute ileitis in ST2 deficient mice. In conclusion, severe lethal ileitis induced by oral T. gondii infection is attenuated by blockade of ST2 signaling and may be mediated in part by endogenous IL-22.
Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucinas/metabolismo , Toxoplasma/metabolismo , Toxoplasmose Animal/metabolismo , Animais , Citocinas/metabolismo , Microbioma Gastrointestinal/fisiologia , Ileíte/metabolismo , Ileíte/parasitologia , Íleo/metabolismo , Íleo/parasitologia , Inflamação/metabolismo , Inflamação/parasitologia , Interferon gama/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Interleucina 22RESUMO
Allergic asthma is characterized by a strong Th2 and Th17 response with inflammatory cell recruitment, airways hyperreactivity and structural changes in the lung. The protease allergen papain disrupts the airway epithelium triggering a rapid eosinophilic inflammation by innate lymphoid cell type 2 (ILC2) activation, leading to a Th2 immune response. Here we asked whether the daily oral administrations of the probiotic Escherichia coli strain Nissle 1917 (ECN) might affect the outcome of the papain protease induced allergic lung inflammation in BL6 mice. We find that ECN gavage significantly prevented the severe allergic response induced by repeated papain challenges and reduced lung inflammatory cell recruitment, Th2 and Th17 response and respiratory epithelial barrier disruption with emphysema and airway hyperreactivity. In conclusion, ECN administration attenuated severe protease induced allergic inflammation, which may be beneficial to prevent allergic asthma.
Assuntos
Alérgenos/administração & dosagem , Asma/prevenção & controle , Escherichia coli/crescimento & desenvolvimento , Fatores Imunológicos/administração & dosagem , Papaína/administração & dosagem , Probióticos/administração & dosagem , Administração Oral , Animais , Asma/induzido quimicamente , Asma/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Respiratória/patologia , Células Th17/imunologia , Células Th2/imunologia , Resultado do TratamentoRESUMO
Host directed immunomodulation represents potential new adjuvant therapies in infectious diseases such as tuberculosis. Major cytokines like TNFα exert a multifold role in host control of mycobacterial infections. GM-CSF and its receptor are over-expressed during acute M. tuberculosis infection and we asked how GM-CSF neutralization might affect host response, both in immunocompetent and in immunocompromised TNFα-deficient mice. GM-CSF neutralizing antibodies, at a dose effectively preventing acute lung inflammation, did not affect M. tuberculosis bacterial burden, but increased the number of granuloma in wild-type mice. We next assessed whether GM-CSF neutralization might affect the control of M. tuberculosis by isoniazid/rifampicin chemotherapy. GM-CSF neutralization compromised the bacterial control under sub-optimal isoniazid/rifampicin treatment in TNFα-deficient mice, leading to exacerbated lung inflammation with necrotic granulomatous structures and high numbers of intracellular M. tuberculosis bacilli. In vitro, GM-CSF neutralization promoted M2 anti-inflammatory phenotype in M. bovis BCG infected macrophages, with reduced mycobactericidal NO production and higher intracellular M. bovis BCG burden. Thus, GM-CSF pathway overexpression during acute M. tuberculosis infection contributes to an efficient M1 response, and interfering with GM-CSF pathway in the course of infection may impair the host inflammatory response against M. tuberculosis.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fatores Imunológicos/metabolismo , Imunomodulação , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/patologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Antituberculosos/administração & dosagem , Bovinos , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Fatores Imunológicos/antagonistas & inibidores , Isoniazida/administração & dosagem , Macrófagos/imunologia , Camundongos , Mycobacterium bovis/imunologia , Rifampina/administração & dosagem , Resultado do Tratamento , Tuberculose Pulmonar/imunologiaRESUMO
BACKGROUND: IL-33 plays a critical role in regulation of tissue homeostasis, injury, and repair. Whether IL-33 regulates neutrophil recruitment and functions independently of airways hyperresponsiveness (AHR) in the setting of ozone-induced lung injury and inflammation is unclear. OBJECTIVE: We sought to examine the role of the IL-33/ST2 axis in lung inflammation on acute ozone exposure in mice. METHODS: ST2- and Il33-deficient, IL-33 citrine reporter, and C57BL/6 (wild-type) mice underwent a single ozone exposure (1 ppm for 1 hour) in all studies. Cell recruitment in lung tissue and the bronchoalveolar space, inflammatory parameters, epithelial barrier damage, and airway hyperresponsiveness (AHR) were determined. RESULTS: We report that a single ozone exposure causes rapid disruption of the epithelial barrier within 1 hour, followed by a second phase of respiratory barrier injury with increased neutrophil recruitment, reactive oxygen species production, AHR, and IL-33 expression in epithelial and myeloid cells in wild-type mice. In the absence of IL-33 or IL-33 receptor/ST2, epithelial cell injury with protein leak and myeloid cell recruitment and inflammation are further increased, whereas the tight junction proteins E-cadherin and zonula occludens 1 and reactive oxygen species expression in neutrophils and AHR are diminished. ST2 neutralization recapitulated the enhanced ozone-induced neutrophilic inflammation. However, myeloid cell depletion using GR-1 antibody reduced ozone-induced lung inflammation, epithelial cell injury, and protein leak, whereas administration of recombinant mouse IL-33 reduced neutrophil recruitment in Il33-deficient mice. CONCLUSION: Data demonstrate that ozone causes an immediate barrier injury that precedes myeloid cell-mediated inflammatory injury under the control of the IL-33/ST2 axis. Thus IL-33/ST2 signaling is critical for maintenance of intact epithelial barrier and inflammation.
Assuntos
Poluentes Atmosféricos/toxicidade , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/imunologia , Lesão Pulmonar/imunologia , Oxidantes/toxicidade , Ozônio/toxicidade , Animais , Feminino , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologiaRESUMO
Reactive oxygen species (ROS) are generated by virus-infected cells; however, the physiological importance of ROS generated under these conditions is unclear. Here we found that the inflammation and cell death induced by exposure of mice or cells to sources of ROS were not altered in the absence of canonical ROS-sensing pathways or known cell-death pathways. ROS-induced cell-death signaling involved interactions among the cellular ROS sensor and antioxidant factor KEAP1, the phosphatase PGAM5 and the proapoptotic factor AIFM1. Pgam5 -/- mice showed exacerbated lung inflammation and proinflammatory cytokines in an ozone-exposure model. Similarly, challenge with influenza A virus led to increased infiltration of the virus, lymphocytic bronchiolitis and reduced survival of Pgam5 -/- mice. This pathway, which we have called 'oxeiptosis', was a ROS-sensitive, caspase independent, non-inflammatory cell-death pathway and was important for protection against inflammation induced by ROS or ROS-generating agents such as viral pathogens.
Assuntos
Morte Celular/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Fator de Indução de Apoptose/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Atopic dermatitis (AD) is a chronic Th2 type inflammatory skin disorder. Here we report that MyD88 signaling is crucial in the pathogenesis of experimental AD induced by vitamin D3 analog MC903. The clinical signs and inflammation caused by MC903 are drastically reduced in MyD88-/- mice with diminished eosinophil, neutrophil infiltration and Th2 cytokine expression. The biological effect of interleukin-1 (IL-1) family members relies on MyD88 signaling. We observed a strong upregulation of IL-1 family cytokine expression, including IL-1α, IL-1ß, IL-33, IL-18, IL-36α, IL-36ß, IL-36γ and IL-36Ra. Therefore, we asked which cytokine of the IL-1 family would be essential for MC903-induced AD syndrome. We find a significant reduction of AD in IL-33-/- and IL-33R/ST2-/- mice, only a minor reduction in double IL-1αß-/- mice and no difference in IL-36R-/- and IL-36Ra-/- mice. IL-33 is expressed in keratinocytes, and MyD88 signaling in dendritic cells (DCs) is crucial for AD development as inflammation was drastically reduced in DC-specific MyD88-/- mice (CD11c-cre × MyD88-floxed). Taken together, the data demonstrate a critical role of MyD88 in DCs and of IL-33 signaling via ST2 in MC903-induced AD. These data suggest that IL-33/IL-33R may be a therapeutic target of AD.