RESUMO
Being overweight exacerbates various metabolic diseases, necessitating the identification of target molecules for obesity control. In the current study, we investigated common physiological features related to metabolism in mice with low weight gain: (1) G protein-coupled receptor, family C, group 5, member B-knockout; (2) gastric inhibitory polypeptide receptor-knockout; and (3) Iroquois-related homeobox 3-knockout. Moreover, we explored genes involved in metabolism by analyzing differentially expressed genes (DEGs) between low-weight gain mice and the respective wild-type control mice. The common characteristics of the low-weight gain mice were low inguinal white adipose tissue (iWAT) and liver weight despite similar food intake along with lower blood leptin levels and high energy expenditure. The DEGs of iWAT, epididymal (gonadal) WAT, brown adipose tissue, muscle, liver, hypothalamus, and hippocampus common to these low-weight gain mice were designated as candidate genes associated with metabolism. One such gene tetraspanin 7 (Tspan7) from the iWAT was validated using knockout and overexpressing mouse models. Mice with low Tspan7 expression gained more weight, while those with high Tspan7 expression gained less weight, confirming the involvement of the Tspan7 gene in weight regulation. Collectively, these findings suggest that the candidate gene list generated in this study contains potential target molecules for obesity regulation. Further validation and additional data from low-weight gain mice will aid in understanding the molecular mechanisms associated with obesity.
Assuntos
Tecido Adiposo Marrom , Obesidade , Camundongos , Animais , Obesidade/genética , Obesidade/metabolismo , Tecido Adiposo Marrom/metabolismo , Aumento de Peso/genética , Tecido Adiposo Branco/metabolismo , Metabolismo Energético/genética , Fenótipo , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica , Camundongos KnockoutRESUMO
Group 2 innate lymphoid cells (ILC2s) elicit ostensibly paradoxical responses, such as tissue repair and stimulation of tumorigenesis. Given emerging evidence that ILC2s also contribute to cancer immunosurveillance, we reassess the role of ILC2s in tumorigenesis and discuss recent insights into their tumoricidal potential.
Assuntos
Imunidade Inata , Neoplasias , Carcinogênese , Transformação Celular Neoplásica , Humanos , Linfócitos , Monitorização ImunológicaRESUMO
Innate lymphoid cells (ILCs) are mostly tissue resident lymphocytes that are preferentially enriched in barrier tissues such as the skin. Although they lack the expression of somatically rearranged antigen receptors present on T and B cells, ILCs partake in multiple immune pathways by regulating tissue inflammation and potentiating adaptive immunity. Emerging evidence indicates that ILCs play a critical role in the control of melanoma, a type of skin malignancy thought to trigger immunity mediated mainly by adaptive immune responses. Here, we compile our current understanding of ILCs with regard to their role as the first line of defence against melanoma development and progression. We also discuss areas that merit further investigation. We envisage that the possibility to harness therapeutic potential of ILCs might benefit patients suffering from skin malignancies such as melanoma.
Assuntos
Homeostase/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Neoplasias/imunologia , Pele/imunologia , HumanosRESUMO
ADP-ribosylation factor (Arf) family consisting of six family members, Arf1-Arf6, belongs to Ras superfamily and orchestrates vesicle trafficking under the control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins. It is well established that brefeldin A, a potent inhibitor of ArfGEFs, blocks cytokine secretion from activated T cells, suggesting that the Arf pathway plays important roles in T cell functions. In this study, because Arf1 and Arf6 are the best-characterized members among Arf family, we established T lineage-specific Arf1-deficient, Arf6-deficient, and Arf1/6 double-deficient mice to understand physiological roles of the Arf pathway in the immune system. Contrary to our expectation, Arf deficiency had little or no impact on cytokine secretion from the activated T cells. In contrast, the lack of both Arf1 and Arf6, but neither Arf1 nor Arf6 deficiency alone, rendered naive T cells susceptible to apoptosis upon TCR stimulation because of imbalanced expression of Bcl-2 family members. We further demonstrate that Arf1/6 deficiency in T cells alleviates autoimmune diseases like colitis and experimental autoimmune encephalomyelitis, whereas Ab response under Th2-polarizing conditions is seemingly normal. Our findings reveal an unexpected role for the Arf pathway in the survival of T cells during TCR-induced activation and its potential as a therapeutic target in the autoimmune diseases.
Assuntos
Fator 1 de Ribosilação do ADP/metabolismo , Fatores de Ribosilação do ADP/metabolismo , Colite/imunologia , Encefalomielite Autoimune Experimental/imunologia , Linfócitos T/imunologia , Fator 1 de Ribosilação do ADP/genética , Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP/genética , Animais , Apoptose , Sobrevivência Celular , Células Cultivadas , Imunoterapia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de SinaisRESUMO
Group 2 innate lymphoid cells (ILC2s) are abundant in non-lymphoid tissues and increase following infectious and inflammatory insults. In solid tumors, however, ILC2s constitute a relatively small proportion of immune cells. Here, we show, using melanoma as a model, that while the IL-33/IL C2/eosinophil axis suppresses tumor growth, tumor-derived lactate attenuates the function and survival of ILC2s. Melanomas with reduced lactate production (LDHAlow) are growth delayed and typified by an increased number of ILC2s compared with control tumors. Upon IL-33 stimulation, ILC2s accompanied by eosinophils more effectively restrain the growth of LDHAlow tumors than control melanomas. Furthermore, database analysis reveals a negative correlation between the expression of LDHA and markers associated with ILC2s and the association of high expression of IL33 and an eosinophil marker SIGLEC8 with better overall survival in human cutaneous melanoma patients. This work demonstrates that the balance between the IL-33/ILC2/eosinophil axis and lactate production by tumor cells regulates melanoma growth.
Assuntos
Imunidade Inata , Ácido Láctico/metabolismo , Linfócitos/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Animais , Proliferação de Células , Sobrevivência Celular , Eosinófilos/imunologia , Feminino , Humanos , Interleucina-33/metabolismo , Interleucina-5/biossíntese , L-Lactato Desidrogenase/metabolismo , Masculino , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BLRESUMO
Three-dimensional (3D) tumor spheroids have the potential to bridge the gap between two-dimensional (2D) monolayer tumor cell cultures and solid tumors with which they share a significant degree of similarity. However, the progression of solid tumors is often influenced by the dynamic and reciprocal interactions between tumor and immune cells. Here we present a 3D tumor spheroid-based model that might shed new light on understanding the mechanisms of tumor and immune cell interactions. The model first utilizes the hanging drop assay, which serves as one of the simplest methods for generating 3D spheroids and requires no specialized equipment. Next, pre-established spheroids can be co-cultured either directly or indirectly with an immune cell population of interest. Using skin melanoma, we provide a detailed description of the model, which might hold a significant importance for the development of successful therapeutic strategies.
RESUMO
Complex interactions between immune cells are an important component in the induction of obesity. Here, we show that Il2rg-/-Rag2-/- mice lacking all lymphocytes are resistant to diet-induced obesity. Transplantation of bone marrow cells from Rag2-/- mice, which lack only acquired immune cells, into Il2rg-/-Rag2-/- mice abolishes this resistance, indicating a role for innate lymphoid cells (ILCs) in this process. Mice lacking ILC2 or ILC3 cells, but not natural killer cells, are resistant to obesity. Adoptive transfer of naive ILC2s isolated from the small intestine (SI), but not ILC2s from white adipose tissue (WAT), restores the induction of diet-induced obesity in Il2rg-/-Rag2-/- mice. Analysis of transcriptional differences reveals that SI-ILC2s express higher levels of IL-2 than do WAT-ILC2s and that blockade of IL-2 signaling impairs weight gain and reduces the populations of ILC2s and ILC3s in the SI, suggesting a role for the IL-2/ILC2/3 axis in the induction of obesity.
Assuntos
Tecido Adiposo Branco/citologia , Interleucina-2/metabolismo , Intestino Delgado/citologia , Linfócitos/citologia , Linfócitos/metabolismo , Obesidade/imunologia , Tecido Adiposo Branco/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica , Microbioma Gastrointestinal/genética , Imunidade Inata , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Intestino Delgado/metabolismo , Células Matadoras Naturais/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
The advance of immunotherapies has revolutionized the treatment of cancer patients. Mostly agents modulating the adaptive immune system are currently used. More recently, attempts to stimulate the innate immune system are being promoted for clinical evaluation. Innate lymphoid cells (ILCs) are a highly plastic population of immune cells crucial for tissue homeostasis and the regulation of immune responses and maybe a promising target to improve current cancer immunotherapies. Although we have made significant progress in understanding ILC biology, their impact on tumor development, progression and therapy is controversial. In this review, we discuss the recent advances of ILC function and plasticity in the context of cancer.
Assuntos
Plasticidade Celular/imunologia , Imunidade Inata , Linfócitos/imunologia , Linfócitos/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Citocinas/metabolismo , Humanos , Imunoterapia , Neoplasias/patologia , Neoplasias/terapiaRESUMO
The immune system plays a dual role in cancer. It conveys protective immunity but also facilitates malignant progression, either by sculpting tumor immunogenicity or by creating a microenvironment that can stimulate tumor outgrowth or aid in a subsequent metastatic cascade. Innate lymphoid cells (ILCs) embody this functional heterogeneity, although the nature of their responses in cancer has only recently begun to be unveiled. We provide an overview of recent insights into the role of ILCs in cancer. We also discuss how ILCs fit into the conceptual framework of cancer immunoediting, which integrates the dual role of the immune system in carcinogenesis. A broader understanding of their relevance in cancer is essential towards the design of successful therapeutic strategies.
Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Neoplasias/imunologia , Animais , Humanos , Linfócitos/patologia , Neoplasias/patologiaRESUMO
Group 2 innate lymphoid cells (ILC2s) play critical roles in the induction of type 2 inflammation, response to parasite infection, metabolic homeostasis, and tissue repair. These multifunctional roles of ILC2s are tightly controlled by complex regulatory systems in the local microenvironment, the disruption of which may cause various health problems. This review summarizes up-to-date knowledge regarding positive and negative regulators for ILC2s based on their function and signaling pathways, including activating cytokines (IL-33, IL-25; MAPK, NF-κB pathways), co-stimulatory cytokines (IL-2, IL-7, IL-9, TSLP; STAT5, IL-4; STAT6, TNF superfamily; MAPK, NF-κB pathways), suppressive cytokines (type1 IFNs, IFN-γ, IL-27; STAT1, IL-10, TGF-ß), transdifferentiation cytokines (IL-12; STAT4, IL-1ß, IL-18), lipid mediators (LTC4, LTD4, LTE4, PGD2; Ca2+ -NFAT pathways, PGE2, PGI2; AC/cAMP/PKA pathways, LXA4, LTB4), neuropeptides (NMU; Ca2+ -NFAT, MAPK pathways, VIP, CGRP, catecholamine, acetylcholine), sex hormones (androgen, estrogen), nutrients (butyrate; HDAC inhibitors, vitamins), and cell-to-cell interactions (ICOSL-ICOS; STAT5, B7-H6-NKp30, E-cadherin-KLRG1). This comprehensive review affords a better understanding of the regulatory network system for ILC2s, providing impetus to develop new treatment strategies for ILC2-related health problems.
Assuntos
Imunidade Inata , Linfócitos/imunologia , Células Th2/imunologia , Animais , Comunicação Celular , Microambiente Celular , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Homeostase , Humanos , NF-kappa B/metabolismo , Transdução de SinaisRESUMO
Group 2 innate lymphoid cells (ILC2s) are derived from common lymphoid progenitors (CLPs) via several specific precursors, and the transcription factors essential for ILC2 differentiation have been extensively studied. However, the external factors regulating commitment to the ILC lineage as well as the sites and stromal cells that constitute the optimal microenvironment for ILC2-specific differentiation are not fully defined. In this study, we demonstrate that three key external factors, the concentration of interleukin 7 (IL-7) and strength and duration of Notch signaling, coordinately determine the fate of CLP toward the T, B, or ILC lineage. Additionally, we identified three stages of ILC2 in the fetal mesentery that require STAT5 signals for maturation: ILC progenitors, CCR9+ ILC2 progenitors, and KLRG1- immature ILC2. We further demonstrate that ILC2 development is supported by mesenteric platelet-derived growth factor receptor α (PDGFRα)+ glycoprotein 38 (gp38)+ mesenchymal cells. Collectively, our results suggest that early differentiation of ILC2 occurs in the fetal liver via IL-7 and Notch signaling, whereas final differentiation occurs in the periphery with the aid of PDGFRα+gp38+ cells.
Assuntos
Diferenciação Celular , Imunidade Inata , Fígado/citologia , Fígado/embriologia , Linfócitos/citologia , Glicoproteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/citologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Feto/citologia , Fator de Transcrição GATA3/metabolismo , Imunidade Inata/efeitos dos fármacos , Interleucina-7/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Mesentério/embriologia , Camundongos Endogâmicos C57BL , Receptores Notch/metabolismo , Transdução de Sinais , Células Estromais/citologia , Células Estromais/metabolismo , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Timo/citologiaRESUMO
Innate lymphoid cells (ILCs) fulfill important protective and reparative functions, and have thus been implicated in the maintenance of tissue homeostasis. Dysregulation of their activation is associated with several autoimmune and inflammatory diseases. The current literature on the role of ILCs in cancer is limited and our knowledge is therefore incomplete. Indeed, ILCs have been separately associated with tumor-promoting as well as tumor-suppressing activities, raising the need to understand the mechanisms by which these cells regulate tumor growth and progression toward a rational design of therapeutic approaches. We focus here on the heterogeneity of ILCs and discuss currently known mechanisms of their plasticity.
Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Neoplasias/imunologia , HumanosRESUMO
Transforming growth factor-ß (TGF-ß) is a pivotal cytokine in the differentiation of regulatory T cells, and Foxo transcription factors positively regulate this process. On the other hand, the function of Foxo transcription factors is negatively regulated by PI3K/Akt signaling, which is activated by TGF-ß in many types of cells; yet the role of TGF-ß in Akt activity and its downstream substrates in CD4+ T cells, including Foxo transcription factors, remains to be determined. Herein, we demonstrate that TGF-ß selectively induces Akt phosphorylation at Ser473 but not at Thr308 in a class IA PI3K-dependent manner in CD4+ T cells, resulting in the phosphorylation and inhibition of Foxo transcription factors and negatively regulating the differentiation of induced regulatory T cells (iTregs). These observations reveal a novel negative regulatory mechanism involving Akt and Foxo transcription factors induced by TGF-ß in the iTreg differentiation process.
Assuntos
Proteína Forkhead Box O1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T Reguladores/citologia , Fator de Crescimento Transformador beta/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Proteína Forkhead Box O3/metabolismo , Fatores de Transcrição Forkhead/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Serina/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Whether Propionibacterium acnes (P. acnes) causes surgical-site infections (SSI) after orthopedic surgery is controversial. We previously reported that we frequently find P. acnes in intraoperative specimens, yet none of the patients have clinically apparent infections. Here, we tracked P. acnes for 6 months in a mouse osteomyelitis model. We inoculated P. acnes with an implant into the mouse femur in the implant group; the control group was treated with the bacteria but no implant. We then observed over a 6-month period using optical imaging system. During the first 2 weeks, bacterial signals were detected in the femur in the both groups. The bacterial signal completely disappeared in the control group within 28 days. Interestingly, in the implant group, bacterial signals were still present 6 months after inoculation. Histological and scanning electron-microscope analyses confirmed that P. acnes was absent from the control group 6 months after inoculation, but in the implant group, the bacteria had survived in a biofilm around the implant. PCR analysis also identified P. acnes in the purulent effusion from the infected femurs in the implant group. To our knowledge, this is the first report showing that P. acnes causes SSI only in the presence of an implant.
Assuntos
Infecções por Bactérias Gram-Positivas/diagnóstico por imagem , Osteomielite/cirurgia , Propionibacterium acnes/fisiologia , Próteses e Implantes/microbiologia , Infecção da Ferida Cirúrgica/microbiologia , Animais , Aderência Bacteriana , Biofilmes/crescimento & desenvolvimento , Modelos Animais de Doenças , Fêmur/diagnóstico por imagem , Fêmur/microbiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Camundongos , Imagem Óptica , Infecção da Ferida Cirúrgica/diagnóstico por imagemRESUMO
Allergic airway inflammation is one of the primary features of allergic asthma. Interleukin-33 (IL-33) is recognized as a key pro-inflammatory cytokine that mediates allergic airway inflammation, and its expression is elevated in this condition, but little is known about the regulatory mechanisms underlying IL-33 induction. Here, we show that the RNA binding protein Mex-3B plays a critical role in the induction of IL-33 in the development of allergic airway inflammation. We generated Mex3b(-/-) mice and found that they develop significantly less airway inflammation than wild-type mice due to reduced induction of IL-33. Furthermore, we show that Mex-3B directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33. Moreover, we show that inhalation of an antisense oligonucleotide targeting Mex-3B suppresses allergic airway inflammation. Our data identify a signaling pathway that post-transcriptionally regulates IL-33 expression and suggest that Mex-3B could be a promising molecular target for the treatment of allergic asthma.
Assuntos
Hiper-Reatividade Brônquica/terapia , Células Epiteliais/efeitos dos fármacos , Interleucina-33/imunologia , MicroRNAs/imunologia , Oligonucleotídeos Antissenso/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Sequência de Bases , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Interleucina-33/genética , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , MicroRNAs/genética , Conformação de Ácido Nucleico , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Ovalbumina , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Transdução de Sinais , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/patologiaRESUMO
Various silver-coated implants have been developed to prevent implant-associated infections, and have shown dramatic effects in vitro. However, the in vivo results have been inconsistent. Recent in vitro studies showed that silver exerts antibacterial activity by mediating the generation of reactive oxygen species in the presence of oxygen. To maintain its antibacterial activity in vivo, the silver should remain in an ionic state and be stably bound to the implant surface. Here, we developed a novel bacteria-resistant hydroxyapatite film in which ionic silver is immobilized via inositol hexaphosphate chelation using a low-heat immersion process. This bacteria-resistant coating demonstrated significant antibacterial activity both in vitro and in vivo. In a murine bioluminescent osteomyelitis model, no bacteria were detectable 21 days after inoculation with S. aureus and placement of this implant. Serum interleukin-6 was elevated in the acute phase in this model, but it was significantly lower in the ionic-silver group than the control group on day 2. Serum C-reactive protein remained significantly higher in the control group than the ionic-silver group on day 14. Because this coating is produced by a low-heat immersion process, it can be applied to complex structures of various materials, to provide significant protection against implant-associated infections.
Assuntos
Quelantes/química , Materiais Revestidos Biocompatíveis/química , Durapatita/química , Ácido Fítico/química , Prata/química , Animais , Proteína C-Reativa/análise , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/farmacologia , Modelos Animais de Doenças , Fêmur/patologia , Interleucina-6/sangue , Íons/química , Medições Luminescentes , Camundongos , Osteomielite/sangue , Osteomielite/prevenção & controle , Osteomielite/veterinária , Próteses e Implantes , Espectrofotometria Atômica , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidadeRESUMO
To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8(.)6% variance explained) in (semi-)supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI) = - 0.795 (- 1.436 to - 0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.
Assuntos
Envelhecimento/genética , Inflamação/genética , Inflamação/mortalidade , Telômero/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Biomarcadores , Causas de Morte , Senescência Celular/genética , Feminino , Humanos , Imunossenescência/genética , Inflamação/epidemiologia , Inflamação/metabolismo , Estimativa de Kaplan-Meier , Longevidade/genética , Estudos Longitudinais , Masculino , MorbidadeRESUMO
House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells.
Assuntos
Inflamação/imunologia , Interleucina-2/imunologia , Interleucinas/imunologia , Mastócitos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Células Cultivadas , Eosinofilia/induzido quimicamente , Humanos , Interleucina-10/imunologia , Interleucina-2/genética , Interleucina-33 , Interleucinas/genética , Interleucinas/farmacologia , Pulmão/citologia , Pulmão/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Papaína/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Pyroglyphidae/imunologia , Células Th2/imunologiaRESUMO
Allergic asthma is an inflammatory disease characterized by lung eosinophilia controlled by type 2 cytokines. Cysteine proteases are potent triggers of allergic inflammation by causing barrier disruption in lung epithelial cells inducing the elevation of interleukin-5 (IL-5) and IL-13 from natural helper (NH) cells, a member of ILC2s, which leads to lung eosinophilia. In this study, we found that basophils play a crucial role in NH cell-mediated eosinophilic inflammation induced by protease allergens. Conditional deletion of basophils caused a resolution of the papain-induced eosinophilia and mucus production. Resolution of eosinophilia was also observed in mice lacking IL-4 specifically in basophils, indicating that basophil-derived IL-4 enhanced expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in NH cells, thus attracting eosinophils. These results demonstrate that IL-4 from basophils has an important role in the NH-derived cytokine and chemokine expression, subsequently leading to protease allergen-induced airway inflammation.
Assuntos
Basófilos/imunologia , Eosinófilos/imunologia , Interleucina-13/imunologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Animais , Asma/imunologia , Quimiocina CCL11/biossíntese , Interleucina-13/biossíntese , Interleucina-4/deficiência , Interleucina-4/genética , Interleucina-5/biossíntese , Interleucina-9/biossíntese , Interleucina-9/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/imunologia , Eosinofilia Pulmonar/imunologia , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
While the 2002-2003 outbreak of severe acute respiratory syndrome (SARS) resulted in 774 deaths, patients who were affected with mild pulmonary symptoms successfully recovered. The objective of the present work was to identify, using SARS coronavirus (SARS-CoV) mouse infection models, immune factors responsible for clearing of the virus. The elimination of pulmonary SARS-CoV infection required the activation of B cells by CD4(+) T cells. Furthermore, passive immunization (post-infection) with homologous (murine) anti-SARS-CoV antiserum showed greater elimination efficacy against SARS-CoV than that with heterologous (rabbit) antiserum, despite the use of equivalent titers of neutralizing antibodies. This distinction was mediated by mouse phagocytic cells (monocyte-derived infiltrating macrophages and partially alveolar macrophages, but not neutrophils), as demonstrated both by adoptive transfer from donors and by immunological depletion of selected cell types. These results indicate that the cooperation of anti-SARS-CoV antibodies and phagocytic cells plays an important role in the elimination of SARS-CoV.