RESUMEN
BACKGROUND: Reinstating inflammation resolution represents an innovative concept to regain inflammation control in diseases marked by chronic inflammation. While most therapeutics target inflammatory molecules and inflammatory effector cells and mediators, targeting macrophages to initiate inflammation resolution to control neuroinflammation has not yet been attempted. Resolution-phase macrophages are critical in the resolution process to regain tissue homeostasis, and are programmed through the presence and elimination of apoptotic leukocytes. Hence, inducing resolution-phase macrophages might represent an innovative therapeutic approach to control and terminate dysregulated neuroinflammation. METHODS: Here, we investigated if the factors released by in vitro induced resolution-phase macrophages (their secretome) are able to therapeutically reprogram macrophages to control neuroinflammation in the model of experimental autoimmune encephalomyelitis (EAE). RESULTS: We found that injection of the pro-resolutive secretome reduced demyelination and decreased inflammatory cell infiltration in the CNS, notably through the in vivo reprogramming of macrophages at the epigenetic level. Adoptive transfer experiments with in vivo or in vitro reprogrammed macrophages using such pro-resolutive secretome confirmed the stability and transferability of this acquired therapeutic activity. CONCLUSIONS: Overall, our data confirm the therapeutic activity of a pro-resolution secretome in the treatment of ongoing CNS inflammation, via the epigenetic reprogramming of macrophages and open with that a new therapeutic avenue for diseases marked by neuroinflammation.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Animales , Enfermedades Neuroinflamatorias , Macrófagos , Inflamación , LeucocitosRESUMEN
Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach.
Asunto(s)
Antineoplásicos/farmacología , Colesterol/metabolismo , Células Dendríticas/metabolismo , Receptores X del Hígado/agonistas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Dendríticas/patología , Femenino , Humanos , Interleucina-3/metabolismo , Receptores X del Hígado/metabolismo , Masculino , Ratones , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT5/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Patulin is the main mycotoxin contaminating apples. During the brewing of alcoholic beverages, this mycotoxin is degraded to ascladiol, which is also the last precursor of patulin. The present study aims (1) to characterize the last step of the patulin biosynthetic pathway and (2) to describe the toxicity of ascladiol. A patE deletion mutant was generated in Penicillium expansum. In contrast to the wild strain, this mutant does not produce patulin but accumulates high levels of E-ascladiol with few traces of Z-ascladiol. This confirms that patE encodes the patulin synthase involved in the conversion of E-ascladiol to patulin. After purification, cytotoxicities of patulin and E- and Z-ascladiol were investigated on human cell lines from liver, kidney, intestine, and immune system. Patulin was cytotoxic for these four cell lines in a dose-dependent manner. By contrast, both E- and Z-ascladiol were devoid of cytotoxicity. Microarray analyses on human intestinal cells treated with patulin and E-ascladiol showed that the latter, unlike patulin, did not alter the whole human transcription. These results demonstrate that E- and Z-ascladiol are not toxic and therefore patulin detoxification strategies leading to the accumulation of ascladiol are good approaches to limit the patulin risk.
Asunto(s)
Furanos/toxicidad , Patulina/biosíntesis , Patulina/toxicidad , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Furanos/metabolismo , Eliminación de Gen , Genes Fúngicos , Células HEK293 , Células HL-60 , Células Hep G2 , Humanos , Isomerismo , Especificidad de Órganos , Penicillium/genética , Penicillium/metabolismoRESUMEN
Epidemiological studies have associated red meat intake with risk of colorectal cancer. Experimental studies explain this positive association by the oxidative properties of heme iron released in the colon. This latter is a potent catalyst for lipid peroxidation, resulting in the neoformation of deleterious aldehydes in the fecal water of heme-fed rats. The toxicity of fecal water of heme-fed rats was associated to such lipid peroxidation. This study demonstrated that fecal water of hemoglobin- and beef-fed rats preferentially induced apoptosis in mouse normal colon epithelial cells than in those carrying mutation on Apc (Adenomatous polyposis coli) gene, considered as preneoplastic. Highlighting the importance of lipid peroxidation and neoformation of secondary aldehydes like 4-hydroxy-2-nonenal (HNE), we optimized the depletion of carbonyl compounds in the fecal water which turned out to abolish the differential apoptosis in both cell lines. To explain the resistance of preneoplastic cells towards fecal water toxicity, we focused on Nrf2, known to be activated by aldehydes, including HNE. Fecal water activated Nrf2 in both cell lines, associated with the induction of Nrf2-target genes related to aldehydes detoxification. However, the antioxidant defense appeared to be higher in preneoplastic cells, favoring their survival, as evidenced by Nrf2 inactivation. Taken together, our results suggest that Nrf2-dependent antioxidant response was involved in the resistance of preneoplastic cells upon exposure to fecal water of hemoglobin- and beef-fed rats. This difference could explain the promoting effect of red meat and heme-enriched diet on colorectal cancer, by initiating positive selection of preneoplastic cells.
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Antioxidantes/metabolismo , Neoplasias Colorrectales/etiología , Hemoglobinas/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Carne Roja/efectos adversos , Aldehídos , Animales , Apoptosis , Colon/metabolismo , Colon/patología , Heces , Inactivación Metabólica , Masculino , Ratones , Factor 2 Relacionado con NF-E2/genética , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Ratas Endogámicas F344RESUMEN
BACKGROUND: The GABARAP family members (GABARAP, GABARAPL1/GEC1 and GABARAPL2 /GATE-16) are involved in the intracellular transport of receptors and the autophagy pathway. We previously reported that GABARAPL1 expression was frequently downregulated in cancer cells while a high GABARAPL1 expression is a good prognosis marker for patients with lymph node-positive breast cancer. METHODS: In this study, we asked using qRT-PCR, western blotting and epigenetic quantification whether the expression of the GABARAP family was regulated in breast cancer by epigenetic modifications. RESULTS: Our data demonstrated that a specific decrease of GABARAPL1 expression in breast cancers was associated with both DNA methylation and histone deacetylation and that CREB-1 recruitment on GABARAPL1 promoter was required for GABARAPL1 expression. CONCLUSIONS: Our work strongly suggests that epigenetic inhibitors and CREB-1 modulators may be used in the future to regulate autophagy in breast cancer cells.
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Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias de la Mama/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Metilación de ADN/genética , Proteínas Asociadas a Microtúbulos/genética , Acetilación , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Autofagia/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Epigenómica , Femenino , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Histonas/metabolismo , Humanos , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Regiones Promotoras GenéticasRESUMEN
Deoxynivalenol (DON) is the most prevalent trichothecene mycotoxin in crops in Europe and North America. DON is often present with other type B trichothecenes such as 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon-X (FX). Although the cytotoxicity of individual mycotoxins has been widely studied, data on the toxicity of mycotoxin mixtures are limited. The aim of this study was to assess interactions caused by co-exposure to Type B trichothecenes on intestinal epithelial cells. Proliferating Caco-2 cells were exposed to increasing doses of Type B trichothecenes, alone or in binary or ternary mixtures. The MTT test and neutral red uptake, respectively linked to mitochondrial and lysosomal functions, were used to measure intestinal epithelial cytotoxicity. The five tested mycotoxins had a dose-dependent effect on proliferating enterocytes and could be classified in increasing order of toxicity: 3-ADON<15-ADON≈DONAsunto(s)
Células Epiteliales/efectos de los fármacos
, Mucosa Intestinal/citología
, Mucosa Intestinal/efectos de los fármacos
, Micotoxinas/toxicidad
, Tricotecenos/toxicidad
, Algoritmos
, Células CACO-2
, Supervivencia Celular/efectos de los fármacos
, Colorantes
, Relación Dosis-Respuesta a Droga
, Sinergismo Farmacológico
, Humanos
, Sales de Tetrazolio
, Tiazoles
RESUMEN
Changes in metabolism of macrophages are required to sustain macrophage activation in response to different stimuli. We showed that the cytokine TGF-ß (transforming growth factor-ß) regulates glycolysis in macrophages independently of inflammatory cytokine production and affects survival in mouse models of sepsis. During macrophage activation, TGF-ß increased the expression and activity of the glycolytic enzyme PFKL (phosphofructokinase-1 liver type) and promoted glycolysis but suppressed the production of proinflammatory cytokines. The increase in glycolysis was mediated by an mTOR-c-MYC-dependent pathway, whereas the inhibition of cytokine production was due to activation of the transcriptional coactivator SMAD3 and suppression of the activity of the proinflammatory transcription factors AP-1, NF-κB, and STAT1. In mice with LPS-induced endotoxemia and experimentally induced sepsis, the TGF-ß-induced enhancement in macrophage glycolysis led to decreased survival, which was associated with increased blood coagulation. Analysis of septic patient cohorts revealed that the expression of PFKL, TGFBRI (which encodes a TGF-ß receptor), and F13A1 (which encodes a coagulation factor) in myeloid cells positively correlated with COVID-19 disease. Thus, these results suggest that TGF-ß is a critical regulator of macrophage metabolism and could be a therapeutic target in patients with sepsis.
Asunto(s)
COVID-19 , Sepsis , Ratones , Animales , Factor de Crecimiento Transformador beta/metabolismo , Lipopolisacáridos/toxicidad , COVID-19/metabolismo , Macrófagos/metabolismo , Sepsis/metabolismo , Inflamación/metabolismo , Citocinas/metabolismo , GlucólisisRESUMEN
The definition of sarcopenia includes both a loss of muscle strength and a decline in functional quality in addition to the loss of muscle protein mass. Multispectral bioimpendance allows bedside assessment of muscle mass. Using this new tool, we performed a pilot study to look for a possible correlation between muscle mass and various tests of muscle strength (grip strength, key-pitch, tip-pinch) and with functional tests (walk speed on 10 meters and Tinetti test). Our study demonstrates a good correlation between muscle mass determined by spectroscopic bioimpendance and muscle strength assessment, but no correlation with functional tests.
Asunto(s)
Espectroscopía Dieléctrica/métodos , Sistemas de Atención de Punto , Sarcopenia/diagnóstico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Fuerza Muscular/fisiología , Músculo Esquelético/metabolismo , Proyectos PilotoRESUMEN
Interferon gamma (IFN-γ) and transforming growth factor beta (TGF-ß), both pleiotropic cytokines, have been long studied and described as critical mediators of the immune response, notably in T cells. One of the investigators who made seminal and critical discoveries in the field of IFN-γ biology is Dr. Howard Young. In this review, we provide an overview of the biology of IFN-γ as well as its role in cancer and autoimmunity with an emphasis on Dr. Young's critical work in the field. We also describe how Dr. Young's work influenced our own research studying the role of TGF-ß in the modulation of immune responses.
Asunto(s)
Interferón gamma , Factor de Crecimiento Transformador beta , Citocinas , Células Tumorales Cultivadas , InmunidadRESUMEN
Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.
Asunto(s)
Infecciones/inmunología , Infecciones/metabolismo , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , COVID-19/inmunología , Humanos , Inmunidad Innata/inmunología , SARS-CoV-2Asunto(s)
Plaquetas/inmunología , Micropartículas Derivadas de Células/inmunología , Células Dendríticas/inmunología , Receptores X del Hígado/inmunología , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/inmunología , Proteínas Angiogénicas/genética , Proteínas Angiogénicas/inmunología , Benzoatos/farmacología , Bencilaminas/farmacología , Plaquetas/citología , Plaquetas/efectos de los fármacos , Micropartículas Derivadas de Células/química , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Regulación de la Expresión Génica , Humanos , Hidrocarburos Fluorados/farmacología , Hidroxicolesteroles/farmacología , Imidazoles/farmacología , Inmunidad Innata , Receptores X del Hígado/agonistas , Receptores X del Hígado/antagonistas & inhibidores , Receptores X del Hígado/genética , FN-kappa B/genética , FN-kappa B/inmunología , Oligodesoxirribonucleótidos/genética , Oligodesoxirribonucleótidos/inmunología , Fenilendiaminas/farmacología , Cultivo Primario de Células , Receptores Acoplados a Proteínas G , Transducción de Señal , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/inmunología , Sulfonamidas/farmacología , Receptor Toll-Like 7/antagonistas & inhibidores , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-ß, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.
Asunto(s)
Factores Biológicos/fisiología , Citofagocitosis/fisiología , Fibroblastos/fisiología , Enfermedades Inflamatorias del Intestino/inmunología , Macrófagos/fisiología , Cicatrización de Heridas/fisiología , Actinas/biosíntesis , Actinas/genética , Animales , Factores Biológicos/farmacología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , División Celular/efectos de los fármacos , Línea Celular , Colitis/inducido químicamente , Colitis/etiología , Colitis/inmunología , Proteínas de Unión al ADN/deficiencia , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/fisiología , Femenino , Fibronectinas/biosíntesis , Fibronectinas/genética , Humanos , Enfermedades Inflamatorias del Intestino/fisiopatología , Enfermedades Inflamatorias del Intestino/terapia , Mucosa Intestinal/citología , Mucosa Intestinal/lesiones , Transfusión de Linfocitos/efectos adversos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Organismos Libres de Patógenos EspecíficosRESUMEN
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Despite appropriate therapy, 20-40% of affected-patients evolve toward end-stage kidney disease (ESKD). Mesangial IgA deposits are the hallmark of IgAN, and complement deposition (C3) seems to differentiate latent IgA mesangial deposits from active IgAN. Atypical hemolytic uremic syndrome (aHUS), another disease in which complement plays an important role, is caused by inherited or acquired deregulation of the alternative pathway (AP) of complement. A subgroup of IgAN shows thrombotic microangiopathy (TMA) lesions in kidney biopsies, the histological characteristic of aHUS. Genetic variants of complement Factor H (CFH), known to be present in aHUS, have been associated with rapidly progressive forms of IgAN and a clinical pattern of aHUS. Genome-wide association studies (GWAS) have confirmed that the 1q32 region, encoding for CFH and its related proteins, is an IgAN susceptibility locus. A 30 year-old man was admitted for seizures and malignant hypertension. The kidney biopsy showed IgAN associated with features of TMA. Despite five plasma exchanges, the patient remained dialysis-dependent, and ESKD was diagnosed. Functional and genetic complement analysis were performed. A monoallelic protein-truncating, likely loss-of-function variant was identified in the CFHR5 gene. Eculizumab is the treatment of aHUS. As it has been successfully used in a few cases of rapidly progressive IgAN, it was decided to administer eculizumab over a period of 12 months in addition to the usual immunosuppression for renal transplantation. After a follow-up of 3 years, there was no clinical disease recurrence. Systematic biologic and genetic screening of complement in individuals with IgAN might be useful to better delineate the role of the AP of complement in renal disease progression, and this may have therapeutic implications.
RESUMEN
To investigate environmental impacts upon colorectal carcinogenesis (CRC) by diet, we assessed two western diet food contaminants: 4-hydroxynonenal (HNE), a major lipid peroxidation product neoformed during digestion, and a mixture of pesticides. We used human colonic cell lines ectopically eliciting varied genetic susceptibilities to CRC: the non-transformed human epithelial colonic cells (HCECs) and their five isogenic cell lines with the loss of APC (Adenomatous polyposis coli) and TP53 (Tumor protein 53) and/or ectopic expression of mutated KRAS (Kristen-ras). These cell lines have been exposed for either for a short time (2-24 h) or for a long period (3 weeks) to 1 µM HNE and/or 10 µM pesticides. After acute exposure, we did not observe any cytotoxicity or major DNA damage. However, long-term exposure to pesticides alone and in mixture with HNE induced clonogenic transformation in normal HCECs, as well as in cells representing later stages of carcinogenesis. It was associated with genotoxic and non-genomic mechanisms (cell growth, metabolic reprogramming, cell mobility and epithelial-mesenchymal transition) depending on genetic susceptibility. This study demonstrated a potential initiating and promoting effect of food contaminants on CRC after long-term exposure. It supports that these contaminants can accelerate carcinogenesis when mutations in oncogenes or tumor suppressor genes occur.
RESUMEN
Aflatoxin B1 (AFB1) is the most potent carcinogen among mycotoxins. Its biosynthesis involves the formation of versicolorin A (VerA), whose chemical structure shares many features with AFB1. Our data revealed significant levels of VerA in foodstuff from Central Asia and Africa. Given this emerging food risk, it was of prime interest to compare the toxic effects of the two mycotoxins against cells originating from the intestinal tract. We used human colon cell lines (Caco-2, HCT116) to investigate the cytotoxic process induced by the two mycotoxins. Contrary to AFB1, a low dose of VerA (1 µM) disturbed the expression level of thousands of genes (18 002 genes). We show that the cytotoxic effects of low doses of VerA (1-20 µM) were stronger than the same low doses of AFB1 in both Caco-2 and HCT116 cell lines. In Caco-2 cells, VerA induced DNA strand breaks that led to apoptosis and reduced DNA replication of dividing cells, consequently inhibiting cell proliferation. Although VerA was able to induce the p53 signaling pathway in p53 wild-type HCT116 cells, its toxicity process did not mainly rely on p53 expression since similar cytotoxic effects were also observed in HCT116 cells that do not express p53. In conclusion, this study provides evidence of the risk of food contamination by VerA and shed light on its toxicological effect on human colon cells.
Asunto(s)
Antraquinonas , Intestinos/química , Micotoxinas , Aflatoxina B1 , Antraquinonas/farmacocinética , Antraquinonas/toxicidad , Células CACO-2 , Carcinógenos , Humanos , Micotoxinas/farmacocinética , Micotoxinas/toxicidadRESUMEN
Unresolved inflammation is a common feature in the pathogenesis of chronic inflammatory/autoimmune diseases. The factors produced by macrophages eliminating apoptotic cells during resolution are crucial to terminate inflammation, and for subsequent tissue healing. We demonstrated here that the factors produced by macrophages eliminating apoptotic cells were sufficient to reboot the resolution of inflammation in vivo, and thus definitively terminated ongoing chronic inflammation. These factors were called SuperMApo and revealed pro-resolutive properties and accelerated acute inflammation resolution, as attested by both increased phagocytic capacities of macrophages and enhanced thioglycollate-induced peritonitis resolution. Activated antigen-presenting cells exposed to SuperMApo accelerated their return to homeostasis and demonstrated pro-regulatory T cell properties. In mice with ongoing collagen-induced arthritis, SuperMApo injection resolved and definitively terminated chronic inflammation. The same pro-resolving properties were observed in human settings in addition to xenogeneic colitis and graft-vs.-host disease modulation, highlighting SuperMApo as a new therapeutic opportunity to circumvent inflammatory diseases.
Asunto(s)
Apoptosis/inmunología , Inflamación/inmunología , Macrófagos Peritoneales/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Colitis/inmunología , Femenino , Homeostasis/inmunología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Peritonitis/inmunología , Fagocitosis/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Early detection and targeted treatments have led to a significant decrease in mortality linked to breast cancer (BC), however, important issues need to be addressed in the future. One of them will be to find new triple negative breast cancer (TNBC) therapeutic strategies, since none are currently efficiently targeting this subtype of BC. Since numerous studies have reported the possibility of targeting the autophagy pathway to treat or limit cancer progression, we analyzed the expression of six autophagy genes (ATG9A, ATG9B, BECLIN1, LC3B, NIX and P62/SQSTM1) in breast cancer tissue, and compared their expression with healthy adjacent tissue. In our study, we observed an increase in ATG9A mRNA expression in TNBC samples from our breast cancer cohort. We also showed that this increase of the transcript was confirmed at the protein level on paraffin-embedded tissues. To corroborate these in vivo data, we designed shRNA- and CRISPR/Cas9-driven inhibition of ATG9A expression in the triple negative breast cancer cell line MDA-MB-436, in order to determine its role in the regulation of cancer phenotypes. We found that ATG9A inhibition led to an inhibition of in vitro cancer features, suggesting that ATG9A can be considered as a new marker of TNBC and might be considered in the future as a target to develop new specific TNBC therapies.
RESUMEN
BACKGROUND: Worldwide, diabetes has become the most common cause of end-stage renal disease (ESRD), yet Swiss data are largely lacking. METHODS: This observational study examined ESRD patients with diabetes mellitus (ESRD-DM) at end of 2009 and 2014. The prevalence and characteristics of ESRD-DM patients were collected in all dialysis facilities in the Canton of Vaud of Switzerland in 2009 and in 2014, and the 5-year mortality rate was assessed. RESULTS: A total of 107 and 140 ESRD-DM patients underwent dialysis at end of 2009 and 2014, respectively. Within the 5-year period a total of 167 incidental ESRD-DM patients required dialysis, corresponding to an estimated incidental rate of 0.84/1000 person-years in the diabetic population. In 2009, all patients with ESRD-DM underwent haemodialysis, decreasing to 96.2% in 2014, with 3.8% on peritoneal dialysis. Age, sex, body mass index, type of diabetes, duration of diabetes, cause of ESRD, dialysis duration, dialysis frequency, vascular access, and glycosylated haemoglobin levels did not differ between 2009 and 2014. In 2014, macrovascular comorbidity was reported more often than in 2009, but not amputations. Haemoglobin level decreased significantly from 117.9 g/l to 112.3 g/l. Calcium-containing phosphate binder and angiotensin-converting enzyme inhibitor use significantly decreased, whereas iron therapy significantly increased with time. The 5-year mortality rate was 61.7%. Five-year survivors were significantly younger and had a higher body mass index. CONCLUSIONS: The growing prevalence of ESRD-DM emphasises that prevention of chronic kidney disease and its progression should be a public health priority in Switzerland.
Asunto(s)
Nefropatías Diabéticas/epidemiología , Fallo Renal Crónico/epidemiología , Anciano , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/terapia , Femenino , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Prevalencia , Diálisis Renal/estadística & datos numéricos , Suiza/epidemiologíaRESUMEN
The GABARAPL1 protein belongs to the ATG8 family whose members are involved in autophagy. Our laboratory previously demonstrated that GABARAPL1 associates with autophagic vesicles, regulates autophagic flux and acts as a tumor suppressor protein in breast cancer. In this study, we aimed to determine whether GABARAPL1 conjugation to autophagosomes is necessary for its tumor suppressive functions using the MCF-7 breast cancer cell line overexpressing GABARAPL1 or a G116A mutant, which is unable to be lipidated and associated to autophagosomes. We show that the G116A mutation impaired GABARAPL1 function in autophagosome/lysosome fusion and inhibited lysosome activity but did not alter MTOR and ULK1 activities or tumor growth in vivo. Our results demonstrate for the first time that GABARAPL1 plays different regulatory functions during early and late stages of autophagy, independently or not of its conjugation to autophagosomes, but its tumor suppressive function appeared to be independent of its conjugation to autophagic vesicles.