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1.
Immunol Invest ; : 1-17, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38721960

RESUMEN

The anti-tumor capacity of natural killer (NK) cells heavily relies on their ability to migrate towards their target cells. This process is based on dynamic actinrearrangement, so-called actin treadmilling, andis tightly regulated by proteins such as cofilin-1. The aim of the present study was to identify the role of cofilin-1 (CFL-1) in the migratory behavior of NK cells and to investigate a possible impact of an obesity-associated micromilieu on these cells, as it is known that obesity correlates with various impaired NK cell functions. CFL-1 was knocked-down via transfection of NK-92 cells with respective siRNAs. Obesity associated micromilieu was mimicked by incubation of NK-92 cells with adipocyte-conditioned medium from human preadipocyte SGBS cells or leptin. Effects on CFL-1 levels, the degree of phosphorylation to the inactive pCFL-1 as well as NK-92 cell motility were analyzed. Surprisingly, siRNA-mediated CFL-1 knockdown led to a significant increase of migration, as determined by enhanced velocity and accumulated distance of migration. No effect on CFL-1 nor pCFL-1 expression levels, proportion of phosphorylation and cell migratory behavior could be demonstrated under the influence of an obesity-associated microenvironment. In conclusion, the results indicate a significant effect of a CFL-1 knockdown on NK cell motility.

2.
J Transl Med ; 20(1): 539, 2022 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-36419167

RESUMEN

BACKGROUND: Posttranslational protein modifications regulate essential cellular processes, including the immune cell activation. Despite known age-related alterations of the phenotype, composition and cytokine profiles of immune cells, the role of acetylation in the aging process of the immune system was not broadly investigated. Therefore, in the current study the effect of acetylation on the protein expression profiles and function of CD8+ T cells from donors of distinct age was analyzed using histone deacetylase inhibitors (HDACi). METHODS: CD8+ T cells isolated from peripheral blood mononuclear cells of 30 young (< 30 years) and 30 old (> 60 years) healthy donors were activated with anti-CD3/anti-CD28 antibodies in the presence and absence of a cocktail of HDACi. The protein expression profiles of untreated and HDACi-treated CD8+ T cells were analyzed using two-dimensional gel electrophoresis. Proteins with a differential expression level (less than 0.66-fold decrease or more than 1.5-fold increase) between CD8+ T cells of young and old donors were identified by matrix-associated laser desorption ionization-time of flight mass spectrometry. Functional enrichment analysis of proteins identified was performed using the online tool STRING. The function of CD8+ T cells was assessed by analyses of cytokine secretion, surface expression of activation markers, proliferative capacity and apoptosis rate. RESULTS: The HDACi treatment of CD8+ T cells increased in an age-independent manner the intracellular acetylation of proteins, in particular cytoskeleton components and chaperones. Despite a strong similarity between the protein expression profiles of both age groups, the functional activity of CD8+ T cells significantly differed with an age-dependent increase in cytokine secretion and expression of activation markers for CD8+ T cells from old donors, which was maintained after HDACi treatment. The proliferation and apoptosis rate of CD8+ T cells after HDACi treatment was equal between both age groups. CONCLUSIONS: Despite a comparable effect of HDACi treatment on the protein signature of CD8+ T cells from donors of different ages, an initial higher functionality of CD8+ T cells from old donors when compared to CD8+ T cells from young donors was detected, which might have clinical relevance.


Asunto(s)
Linfocitos T CD8-positivos , Histonas , Leucocitos Mononucleares , Inhibidores de Histona Desacetilasas/farmacología , Citocinas
3.
Eur J Immunol ; 48(9): 1592-1594, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30028015

RESUMEN

Chemokine CCL14 is inactive in its proform. Here, we show that inflammation- and cancer-associated kallikrein-related peptidases KLK5 and KLK8 remove the N-terminal eight amino acids from the proform thereby converting CCL14 to its active state. Activity of the chemokine is demonstrated by migration of myeloid cells expressing relevant receptors.


Asunto(s)
Quimiocinas CC/metabolismo , Quimiocinas/metabolismo , Calicreínas/metabolismo , Asma/patología , Aterosclerosis/patología , Línea Celular Tumoral , Quimiocina CX3CL1/metabolismo , Quimiocina CXCL12/metabolismo , Enfermedad de Crohn/patología , Activación Enzimática , Humanos , Interleucina-8/metabolismo , Leucemia/patología , Proteínas Inflamatorias de Macrófagos/metabolismo , Pancreatitis/patología , Especies Reactivas de Oxígeno/metabolismo
4.
Rheumatology (Oxford) ; 58(12): 2325-2329, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31257448

RESUMEN

OBJECTIVE: In autoimmune arthritis, TCR signalling is attenuated by peripheral tolerance mechanisms. We have described previously a population of inhibitory receptor LIR-1 expressing autoreactive CD8+ T cells in rheumatoid arthritis. Here, we investigated the role of CD8+ T cells in murine autoimmune arthritis by analysing their expression of the mouse orthologue of LIR-1, PIR-B. METHODS: Frequencies of PIR-B+CD8+ T cells were determined in the SKG arthritis model. The phenotype of those cells was determined ex vivo by FACS and functionality was investigated by means of cytokine production and cytolytic potential upon activation in vitro. RESULTS: SKG mice, under non-SPF (specific pathogen-free) conditions with clinical symptoms of arthritis, were found to harbour significantly increased frequencies of PIR-B+CD8+ T cells. Those cells showed a pro-inflammatory phenotype with preferential production of IL-17 and IFN-γ. The frequency of those cells correlated inversely with the arthritis score, indicating that they might represent autoreactive, but functionally inhibited, CD8+ T cells. CONCLUSION: PIR-B+CD8+ T cells from SKG mice show a cytotoxic and pro-inflammatory phenotype. Inhibition of CD8+ T cell autoreactivity by PIR-B/LIR-1 receptor signalling might be a counter-regulatory mechanism to curb autoreactivity and arthritis.


Asunto(s)
Artritis Experimental , Artritis Reumatoide/inmunología , Enfermedades Autoinmunes/inmunología , Linfocitos T CD8-positivos/inmunología , Receptores Inmunológicos/biosíntesis , Linfocitos T Citotóxicos/inmunología , Animales , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Citometría de Flujo , Receptor Leucocitario Tipo Inmunoglobulina B1/biosíntesis , Glicoproteínas de Membrana , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Citotóxicos/patología
5.
Eur J Immunol ; 47(9): 1457-1467, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28664612

RESUMEN

The chronic, destructive autoimmune arthritis in SKG mice, which closely resembles human rheumatoid arthritis, is the result of self-reactive T cells escaping thymic deletion. Since the inhibitory receptor LIR-1 is up-regulated on auto-reactive T cells in human rheumatoid arthritis, the role of its murine ortholog PIR-B was investigated. Peripheral CD4+ T cells from SKG mice were found to frequently express PIR-B, and this population produces more frequently IL-17 upon in vitro stimulation compared to PIR-B- cells. A much larger fraction of PIR-B+ T cells, however, was found to secret no IL-17, but IFN-γ. With regards to the clinical course of the disease, high frequencies of PIR-B+ CD4+ T cells were found to be associated with a milder course of arthritis, suggesting that the net effect of PIR-B expression is suppression of autoreactive T cells. Our results indicate that overexpression of PIR-B on IL-17-producing SKG CD4+ T cells might represent an effective counter-regulatory mechanism against the destructive potential of those cells. More importantly, a major population of PIR-B+ T cells in SKG mice appears to play an inhibitory role by way of their IFN-γ production, since high frequencies of those cells ameliorate the disease.


Asunto(s)
Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Linfocitos T CD4-Positivos/inmunología , Interferón gamma/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Antígenos CD/metabolismo , Células Cultivadas , Femenino , Humanos , Interleucina-17/metabolismo , Receptor Leucocitario Tipo Inmunoglobulina B1 , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos , ARN Interferente Pequeño/genética , Receptores Inmunológicos/genética
6.
Hum Mol Genet ; 24(11): 3119-32, 2015 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-25712132

RESUMEN

Chordin-Like 1 (CHRDL1) mutations cause non-syndromic X-linked megalocornea (XMC) characterized by enlarged anterior eye segments. Mosaic corneal degeneration, presenile cataract and secondary glaucoma are associated with XMC. Beside that CHRDL1 encodes Ventroptin, a secreted bone morphogenetic protein (BMP) antagonist, the molecular mechanism of XMC is not well understood yet. In a family with broad phenotypic variability of XMC, we identified the novel CHRDL1 frameshift mutation c.807_808delTC [p.H270Wfs*22] presumably causing CHRDL1 loss of function. Using Xenopus laevis as model organism, we demonstrate that chrdl1 is specifically expressed in the ocular tissue at late developmental stages. The chrdl1 knockdown directly resembles the human XMC phenotype and confirms CHRDL1 deficiency to cause XMC. Interestingly, secondary to this bmp4 is down-regulated in the Xenopus eyes. Moreover, phospho-SMAD1/5 is altered and BMP receptor 1A is reduced in a XMC patient. Together, we classify these observations as negative-feedback regulation due to the deficient BMP antagonism in XMC. As CHRDL1 is preferentially expressed in the limbal stem cell niche of adult human cornea, we assume that CHRDL1 plays a key role in cornea homeostasis. In conclusion, we provide novel insights into the molecular mechanism of XMC as well as into the specific role of CHRDL1 during cornea organogenesis, among others by the establishment of the first XMC in vivo model. We show that unravelling monogenic cornea disorders like XMC-with presumably disturbed cornea growth and differentiation-contribute to the identification of potential limbal stem cell niche factors that are promising targets for regenerative therapies of corneal injuries.


Asunto(s)
Enfermedades Hereditarias del Ojo/genética , Proteínas del Ojo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Animales , Secuencia de Bases , Proteína Morfogenética Ósea 4/genética , Proteína Morfogenética Ósea 4/metabolismo , Córnea/patología , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura , Expresión Génica , Estudios de Asociación Genética , Humanos , Masculino , Linaje , Transducción de Señal , Xenopus laevis
7.
Cancer Immunol Immunother ; 64(4): 519-26, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25680628

RESUMEN

It has become evident that combinatorial treatments with "old fashioned" chemo- and radiotherapy together with DC vaccines, T cell-based approaches therapy by small molecules or novel immunotherapeutic strategies with antibodies are the most promising approaches, but the combinations and sequence of administration has still to be investigated and appear to be tumor specific.


Asunto(s)
Alergia e Inmunología , Vacunas contra el Cáncer/uso terapéutico , Inmunoterapia/métodos , Oncología Médica , Neoplasias/inmunología , Neoplasias/terapia , Animales , Vacunas contra el Cáncer/inmunología , Congresos como Asunto , Humanos , Inmunoterapia/tendencias , Terapia Molecular Dirigida
8.
J Transl Med ; 12: 151, 2014 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-24885059

RESUMEN

BACKGROUND: The importance of B7-H molecules for the T cell/tumor communication and its impact on renal cell carcinoma (RCC) progression and prognosis has been recently described. Cytokine treatment of RCC has earlier been shown to be beneficial in preclinical settings, but its clinical implementation has not proven to be as effective. This might be partially explained by the yet incomplete picture of cellular alterations in tumor cells upon cytokine treatment investigated in detail in this study. METHODS: RCC tumor cell lines were treated with different cytokines alone or in combination. The constitutive and/or cytokine-induced expression of cytokine receptors signaling components and B7-H molecules in RCC cells were analysed by qPCR and flow cytometry. A mcherry reporter gene construct containing B7-H1 promoter was cloned and its activity was determined upon transfection in cytokine-stimulated cells. Cytokine pretreated tumor cells were co-cultured with allogeneic CD8+ T cells from healthy donors and T cell proliferation as well as cytokine secretion was determined. RESULTS: A heterogeneous, but constitutive B7-H1,-H2,-H3 and H4 expression was found on human RCC cell lines. IL-4 and TNFα treatment led to strong synergistic induction of B7-H1 in RCC cells, whereas B7-H2 was only increased by TNFα. In contrast, B7-H3 and B7-H4 expression were not altered by these cytokines. Treatment of RCC cells with TNFα and IL-4 was accompanied by an activation of signaling molecules like NF-κB, IκB and STAT6. The cytokine-mediated up-regulation of B7-H1 was due to transcriptional control as determined by an increased B7-H1 promoter activity in the presence of IL-4 and TNFα. Despite HLA class I and LFA-1 were also increased, the cytokine-mediated up-regulation of B7-H1 was more pronounced and caused an inhibition of allospecifc CD8+ T cell proliferation. CONCLUSION: Thus, IL-4 and TNFα, which could be released by immune cells of the tumor microenvironment, are able to control the B7-H1 expression in RCC thereby altering T cell responses. These data are of importance for understanding the complex interplay of tumor cells with immune cells orchestrated by a number of different soluble and membrane bound mediators and for the implementation of check point antibodies directed against B7-H1.


Asunto(s)
Antígeno B7-H1/biosíntesis , Carcinoma de Células Renales/patología , Interleucina-4/farmacología , Neoplasias Renales/patología , Linfocitos T/citología , Factor de Necrosis Tumoral alfa/farmacología , Secuencia de Bases , Carcinoma de Células Renales/inmunología , Línea Celular Tumoral , Proliferación Celular , Cartilla de ADN , Humanos , Neoplasias Renales/inmunología
9.
Arthritis Rheum ; 64(6): 1740-9, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22183424

RESUMEN

OBJECTIVE: Expansion of autoreactive CD4+CD28(null) T cells is associated with extraarticular disease manifestations, including rheumatoid vasculitis, and it has recently been demonstrated that expansion of these T cells is associated with anticytomegalovirus (anti-CMV) seropositivity. This study was undertaken to investigate a possible link between latent CMV infection and rheumatoid arthritis (RA). METHODS: In a retrospective analysis, anti-CMV antibodies and clinical, serologic, and radiologic parameters of joint destruction were examined in 202 RA patients and 272 healthy controls. In addition, frequencies of CD4+CD28(null) T cells; concentrations of the cytokines monocyte chemotactic protein 1 (MCP-1), interferon-α (IFNα), and IFN-inducible protein 10; and anti-CMV-specific T cell responses were analyzed in RA patients. RESULTS: Overall, no significant difference in the frequency of anti-CMV seropositivity between RA patients and healthy controls was observed. Among individuals older than age 55 years, however, anti-CMV IgG antibodies were significantly more frequent in RA patients than controls (65.3% and 54.7%, respectively; P = 0.05). Anti-CMV seropositivity in RA patients was associated with an increased frequency of CD4+CD28(null) T cells and increased serum concentrations of MCP-1. The frequency of anti-CMV-specific CD4+ T cells producing IFNγ was increased in RA patients compared to controls. Most importantly, anti-CMV-seropositive RA patients showed radiographic evidence of more advanced joint destruction and had increased frequencies of joint-related surgical procedures, indicating more severe joint disease. CONCLUSION: Our findings indicate that latent CMV infection aggravates the clinical course of RA and is associated with increased frequencies of CD4+CD28(null) T cells and of CMV-specific IFNγ-secreting CD4+ T cells.


Asunto(s)
Artritis Reumatoide/inmunología , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Articulaciones/patología , Anciano , Artritis Reumatoide/complicaciones , Artritis Reumatoide/patología , Artritis Reumatoide/cirugía , Antígenos CD28/inmunología , Linfocitos T CD4-Positivos/inmunología , Quimiocina CCL2/sangre , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/patología , Femenino , Humanos , Articulaciones/cirugía , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
10.
Cancer Immunol Immunother ; 61(8): 1327-41, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22695874

RESUMEN

The modulation and suppression of anti-tumor immune responses is a characteristic feature of tumor cells to escape immune surveillance. Members of the B7 family are involved in this process, since the level of activation of the anti-tumor immune response depends on the balance between co-stimulatory and co-inhibitory signals. Some molecules are often overexpressed in tumors, which has been associated with the pathogenesis and progression of malignancies as well as their immunological and non-immunological functions. The B7 homologs play a key role in the maintenance of self-tolerance and the regulation of both innate and adaptive immunity in tumor-bearing hosts. Furthermore, the blockade of negative signals mediated by the interaction of co-inhibitory ligands and counter-receptors of the B7 family is currently being studied as a potential immunotherapeutic strategy for the treatment of cancer in humans.


Asunto(s)
Antígenos B7/inmunología , Activación de Linfocitos/inmunología , Neoplasias/inmunología , Linfocitos T/inmunología , Animales , Antígenos B7/metabolismo , Congresos como Asunto , Humanos , Neoplasias/metabolismo , Linfocitos T/metabolismo
11.
Crit Rev Immunol ; 31(5): 379-446, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22142165

RESUMEN

Lipopolysaccharide (LPS) from Gram-negative bacteria is one of the most potent innate immune-activating stimuli known. Here we review the current understanding of LPS effects on human monocyte and macrophage function. We provide an overview of LPS signal transduction with attention given to receptor cooperativity and species differences in LPS responses, as well as the role of tyrosine phosphorylation and lysine acetylation in signalling. We also review LPS-regulated transcription, with emphasis on chromatin remodeling and primary versus secondary transcriptional control mechanisms. Finally, we review the regulation and function of LPS-inducible cytokines produced by human monocytes and macrophages including TNFα, the IL-1 family, IL-6, IL-8, the IL-10 family, the IL-12 family, IL-15 and TGFß.


Asunto(s)
Citocinas , Lipopolisacáridos , Macrófagos , Monocitos , Receptor Toll-Like 4/metabolismo , Acetilación , Animales , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Citocinas/biosíntesis , Citocinas/inmunología , Humanos , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Lisina/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Modelos Biológicos , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Fosforilación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Especificidad de la Especie , Tirosina/metabolismo , Células U937
13.
Front Nutr ; 8: 711824, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34368213

RESUMEN

Background: The association of obesity and an increased risk for severe infections and various cancer types is well-described. Natural killer (NK) cells are circulating lymphoid cells and promoters of the immune response toward viruses and malignant cells. As demonstrated in previous studies the phenotype and functionality of NK cells is impaired in obesity. So far, the majority of animal studies were exclusively performed using ad libitum feeding regimes and it remained unclear whether NK cell alterations are mediated by obesity-associated immunological changes or by direct effects of the dietary composition. Therefore, the aim of the present study was to characterize NK cells in the peripheral blood of obese-resistant BALB/c mice supplied a normal-fat diet (NFD) or high-fat diet (HFD), ad libitum or in a restrictive manner. Methods: Twenty-eight BALB/c-mice were fed a NFD or HFD either ad libitum or in a restrictive feeding regime with 90% of the mean daily diet supply of the corresponding ad libitum group (each group n = 7). Blood and visceral adipose tissue were collected for flow cytometric analysis, analysis of plasma cytokine concentrations by multiplex immunoassay and real-time RT-PCR analyses. For statistical analyses two-way ANOVA with the factors "feeding regime" and "diet" was performed followed by a post-hoc Tukey's multiple comparison test and to compare means of the four mouse groups. Results: Ad libitum-feeding of a HFD in BALB/c mice has no influence on body weight gain, visceral fat mass, plasma cytokine concentrations, immune cell populations as well as the number, frequency and phenotype of NK cells. In contrast, restrictive feeding of a HFD compared to NFD led to significantly higher body weights, visceral fat mass and plasma interferon-γ concentrations which was associated with changes in the frequencies of granulocytes and NK cell subsets as well as in the surface expression of NK cell maturation markers. Conclusion: Results demonstrate for the first time that HFD-induced alterations in NK cells are consequences of the obese associated immunological profile rather than a direct effect of the dietary composition. These data can help to clarify the increased risk for cancer and severe infections in obesity.

14.
Front Immunol ; 11: 245, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32231659

RESUMEN

Obesity is accompanied by a systemic chronic low-grade inflammation as well as dysfunctions of several innate and adaptive immune cells. Recent findings emphasize an impaired functionality and phenotype of natural killer (NK) cells under obese conditions. This review provides a detailed overview on research related to overweight and obesity with a particular focus on NK cells. We discuss obesity-associated alterations in subsets, distribution, phenotype, cytotoxicity, cytokine secretion, and signaling cascades of NK cells investigated in vitro as well as in animal and human studies. In addition, we provide recent insights into the effects of physical activity and obesity-associated nutritional factors as well as the reduction of body weight and fat mass on NK cell functions of obese individuals. Finally, we highlight the impact of impaired NK cell physiology on obesity-associated diseases, focusing on the elevated susceptibility for viral infections and increased risk for cancer development and impaired treatment response.


Asunto(s)
Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Obesidad/inmunología , Virosis/inmunología , Animales , Citotoxicidad Inmunológica , Susceptibilidad a Enfermedades , Humanos , Vigilancia Inmunológica , Riesgo
15.
Front Nutr ; 7: 585693, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33330585

RESUMEN

Overweight and obesity are major public health challenges worldwide. Obesity is associated with a higher risk for the development of several cancer types, but specific mechanisms underlying the link of obesity and cancer are still unclear. Natural killer (NK) cells are circulating lymphoid cells promoting the elimination of virus-infected and tumor cells. Previous investigations demonstrated conflicting results concerning the influence of obesity on functional NK cell parameters in small animal models. The aim of the present study was to clarify potential obesity-associated alterations of murine NK cells in vivo, implementing different feeding regimes. Therefore, C57BL/6 mice were fed a normal-fat diet (NFD) or high-fat diet (HFD) under restrictive and ad libitum feeding regimes. Results showed diet and feeding-regime dependent differences in body weight, visceral fat mass and plasma cytokine concentrations. Flow cytometry analyses demonstrated significant changes in total cell counts as well as frequencies of immune cell populations in peripheral blood comparing mice fed NFD or HFD in an ad libitum or restrictive manner. Mice fed the HFD showed significantly decreased frequencies of total NK cells and the mature CD11b+CD27+ NK cell subset compared to mice fed the NFD. Feeding HFD resulted in significant changes in the expression of the maturation markers KLRG1 and CD127 in NK cells. Furthermore, real-time PCR analyses of NK-cell related functional parameters in adipose tissue revealed significant diet and feeding-regime dependent differences. Most notable, real-time cytotoxicity assays demonstrated an impaired cytolytic activity of splenic NK cells toward murine colon cancer cells in HFD-fed mice compared to NFD-fed mice. In conclusion, our data demonstrate that feeding a high-fat diet influences the frequency, phenotype and function of NK cells in C57BL/6 mice. Interestingly, restricted feeding of HFD compared to ad libitum feeding resulted in a partial prevention of the obesity-associated alterations on immune cells and especially on NK cells, nicely fitting with the current concept of an advantage for interval fasting for improved health.

16.
Front Immunol ; 11: 573200, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33101297

RESUMEN

Obesity is associated with an increased risk for several cancer types and an altered phenotype and functionality of natural killer (NK) cells. This study aimed to investigate the association of overweight and obesity with NK cell functions and receptor expression profiles in humans. Therefore, peripheral blood mononuclear cells were isolated from normal weight, overweight, and obese healthy blood donors. In depth analysis of immune cell populations and 23 different surface markers, including NK cell receptors, NK-cell-related markers as well as functional intracellular markers on total NK cells and NK subgroups were performed by multicolor flow cytometry. The data revealed a decreased expression of the activating NK cell receptors KIR2DS4 and NKp46 as well as an increased expression of the inhibitory NK cell receptors NKG2A and Siglec-7 in overweight and obese compared to normal weight individuals. Additionally, the expression of the adhesion molecule CD62L and the maturation and differentiation marker CD27 was downregulated in NK cells of overweight and obese subjects. Furthermore, the cytotoxicity of NK cells against colorectal cancer cells was decreased in overweight and obese subjects. Investigations on underlying killing mechanisms demonstrated a reduced TRAIL expression on NK cells of obese subjects suggesting an impaired death receptor pathway in obesity. The present study gives new insights into an impaired functionality and phenotype of NK cells and NK cell subsets in overweight and obesity. These phenotypic alterations and dysfunction of NK cells might be an explanation for the increased cancer risk in obesity.


Asunto(s)
Células Asesinas Naturales/metabolismo , Subgrupos Linfocitarios/metabolismo , Obesidad/metabolismo , Receptores Inmunológicos/metabolismo , Adulto , Anciano , Antígenos de Diferenciación Mielomonocítica/metabolismo , Estudios de Casos y Controles , Degranulación de la Célula , Técnicas de Cocultivo , Citocinas/metabolismo , Citotoxicidad Inmunológica , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Células K562 , Células Asesinas Naturales/inmunología , Selectina L/metabolismo , Lectinas/metabolismo , Subgrupos Linfocitarios/inmunología , Células MCF-7 , Masculino , Persona de Mediana Edad , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Obesidad/diagnóstico , Obesidad/inmunología , Fenotipo , Receptores KIR/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Adulto Joven
17.
Sci Rep ; 10(1): 20606, 2020 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-33244094

RESUMEN

Obesity is a widely spread disease and a crucial risk factor for malign disorders, including breast cancer of women in the postmenopause. Studies demonstrated that in case of obesity crucial natural killer (NK) cell functions like combating tumor cells are affected. This study aims to analyze NK cells and NK cell receptor expression of obese mice in a model for postmenopausal breast cancer. Therefore, female BALB/c mice were fed either a high fat or a standard diet. Thereafter, ovaries were ectomized and a syngeneic and orthotopical injection of 4T1-luc2 mouse mammary tumor cells into the mammary adipose tissue pad was performed. Obese mice showed increased body weights and visceral fat mass as well as increased levels of leptin and IL-6 in plasma. Moreover, compared to the lean littermates, tumor growth was increased and the NKp46-expression on circulating NK cells was decreased. Furthermore, the activating NK cell receptor NKG2D ligand (MULT1) expression was enhanced in adipose tissue of obese tumor bearing mice. The present study gives novel insights into gene expression of NK cell receptors in obesity and aims to promote possible links of the obesity-impaired NK cell physiology and the elevated breast cancer risk in obese women.


Asunto(s)
Células Asesinas Naturales/patología , Neoplasias Mamarias Animales/complicaciones , Obesidad/complicaciones , Animales , Neoplasias de la Mama/sangre , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Antígenos de Histocompatibilidad Clase I/análisis , Interleucina-6/sangre , Leptina/sangre , Neoplasias Mamarias Animales/sangre , Neoplasias Mamarias Animales/patología , Proteínas de la Membrana/análisis , Ratones , Ratones Endogámicos BALB C , Ratones Obesos , Obesidad/sangre , Obesidad/patología , Posmenopausia
18.
Ageing Res Rev ; 62: 101091, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32454090

RESUMEN

Fighting the current COVID-19 pandemic, we must not forget to prepare for the next. Since elderly and frail people are at high risk, we wish to predict their vulnerability, and intervene if possible. For example, it would take little effort to take additional swabs or dried blood spots. Such minimally-invasive sampling, exemplified here during screening for potential COVID-19 infection, can yield the data to discover biomarkers to better handle this and the next respiratory disease pandemic. Longitudinal outcome data can then be combined with other epidemics and old-age health data, to discover the best biomarkers to predict (i) coping with infection & inflammation and thus hospitalization or intensive care, (ii) long-term health challenges, e.g. deterioration of lung function after intensive care, and (iii) treatment & vaccination response. Further, there are universal triggers of old-age morbidity & mortality, and the elimination of senescent cells improved health in pilot studies in idiopathic lung fibrosis & osteoarthritis patients alike. Biomarker studies are needed to test the hypothesis that resilience of the elderly during a pandemic can be improved by countering chronic inflammation and/or removing senescent cells. Our review suggests that more samples should be taken and saved systematically, following minimum standards, and data be made available, to maximize healthspan & minimize frailty, leading to savings in health care, gains in quality of life, and preparing us better for the next pandemic, all at the same time.


Asunto(s)
Envejecimiento/inmunología , Biomarcadores , Infecciones por Coronavirus , Inflamación/diagnóstico , Tamizaje Masivo/métodos , Pandemias , Neumonía Viral , Anciano , Betacoronavirus , COVID-19 , Fragilidad , Humanos , Calidad de Vida , SARS-CoV-2
19.
Cell Death Dis ; 11(1): 12, 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31907350

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

20.
Cell Death Dis ; 10(9): 622, 2019 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-31417078

RESUMEN

The inflammasome is a multiprotein complex assembled in response to Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPs). Inflammasome activation occurs through a two-step mechanism, with the first signal facilitating priming of inflammasome components while the second signal triggers complex assembly. Once assembled, the inflammasome recruits and activates pro-caspase-1, which in turn processes pro-interleukin (IL)-18 and pro-IL-1ß into their bio-active forms. Owing to its key role in the regulation of innate immune responses, the inflammasome has emerged as a therapeutic target for the treatment of inflammatory conditions. In this study we demonstrate that IRE1α, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1α RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1ß processing. These results underscore both the importance and potential therapeutic relevance of targeting IRE1α signaling in conditions of excessive inflammasome formation.


Asunto(s)
Endorribonucleasas/antagonistas & inhibidores , Inflamasomas/metabolismo , Interleucina-1/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Precursores de Proteínas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Humanos , Inflamasomas/efectos de los fármacos , Lipopolisacáridos/farmacología , Nigericina/farmacología , Transducción de Señal , Células THP-1 , Transfección
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