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Langerhans cells (LCs) are distinct among phagocytes, functioning both as embryo-derived, tissue-resident macrophages in skin innervation and repair and as migrating professional antigen-presenting cells, a function classically assigned to dendritic cells (DCs). Here, we demonstrate that both intrinsic and extrinsic factors imprint this dual identity. Using ablation of embryo-derived LCs in the murine adult skin and tracking differentiation of incoming monocyte-derived replacements, we found intrinsic intraepidermal heterogeneity. We observed that ontogenically distinct monocytes give rise to LCs. Within the epidermis, Jagged-dependent activation of Notch signaling, likely within the hair follicle niche, provided an initial site of LC commitment before metabolic adaptation and survival of monocyte-derived LCs. In the human skin, embryo-derived LCs in newborns retained transcriptional evidence of their macrophage origin, but this was superseded by DC-like immune modules after postnatal expansion. Thus, adaptation to adult skin niches replicates conditioning of LC at birth, permitting repair of the embryo-derived LC network.
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Diferenciación Celular , Células de Langerhans , Monocitos , Piel , Células de Langerhans/inmunología , Células de Langerhans/citología , Animales , Monocitos/inmunología , Monocitos/citología , Diferenciación Celular/inmunología , Humanos , Piel/inmunología , Piel/citología , Ratones , Ratones Endogámicos C57BL , FemeninoRESUMEN
Traumatic brain injury (TBI) is a leading cause of disability and increases the risk of developing neurodegenerative diseases. The mechanisms linking TBI to neurodegeneration remain to be defined. It has been proposed that the induction of cellular senescence after injury could amplify neuroinflammation and induce long-term tissue changes. The induction of a senescence response post-injury in the immature brain has yet to be characterised. We carried out two types of brain injury in juvenile CD1 mice: invasive TBI using controlled cortical impact (CCI) and repetitive mild TBI (rmTBI) using weight drop injury. The analysis of senescence-related signals showed an increase in γH2AX-53BP1 nuclear foci, p53, p19ARF, and p16INK4a expression in the CCI group, 5 days post-injury (dpi). At 35 days, the difference was no longer statistically significant. Gene expression showed the activation of different senescence pathways in the ipsilateral and contralateral hemispheres in the injured mice. CCI-injured mice showed a neuroinflammatory early phase after injury (increased Iba1 and GFAP expression), which persisted for GFAP. After CCI, there was an increase at 5 days in p16INK4, whereas in rmTBI, a significant increase was seen at 35 dpi. Both injuries caused a decrease in p21 at 35 dpi. In rmTBI, other markers showed no significant change. The PCR array data predicted the activation of pathways connected to senescence after rmTBI. These results indicate the induction of a complex cellular senescence and glial reaction in the immature mouse brain, with clear differences between an invasive brain injury and a repetitive mild injury.
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Conmoción Encefálica , Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Ratones , Animales , Conmoción Encefálica/complicaciones , Enfermedades Neuroinflamatorias , Lesiones Traumáticas del Encéfalo/complicaciones , Senescencia Celular , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
BACKGROUND AND OBJECTIVES: Aging is known to exacerbate neuroinflammation, and in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), an older age is associated with a worse prognosis. We have previously shown the activation of cell senescence pathways in the proteome of peripheral blood mononuclear cells and the increase of proinflammatory cytokines in blood from individuals living with ALS. In this single-center, retrospective study, we investigated the expression of senescent-like blood mononuclear cells in ALS. METHODS: We first applied multidimensional cytometry by time-of-flight (CyTOF) to study the senescent immunophenotype of blood mononuclear cells from 21 patients with ALS and 10 healthy controls (HCs). We then used targeted flow cytometry (FC) to investigate frequencies of senescent blood lymphocytes in 40 patients with ALS and 20 HCs. Longitudinal analysis included 2 additional time points in 17 patients with ALS. Frequencies of senescent-like lymphocytes were analyzed in relation to survival. RESULTS: Unsupervised clustering of CyTOF data showed higher frequencies of senescent CD4+CD27-CD57+ T cells in patients with ALS compared with those in HCs (p = 0.0017, false discovery (FDR)-adjusted p = 0.029). Moderate to strong negative correlations were identified between CD4 T central memory-cell frequencies and survival (R = -061, p = 0.01; FDR-adjusted p < 0.1) and between CD95 CD8 cells and ALS functional rating scale revised at baseline (R = -0.72, p = 0.001; FDR-adjusted p < 0.1).Targeted FC analysis showed higher memory T regulatory cells (p = 0.0052) and memory CD8+ T cell (M-Tc; p = 0.0006) in bulbar ALS (A-B) compared with those in limb ALS (A-L), while late memory B cells (LM-B) were also elevated in A-B and fast-progressing ALS (p = 0.0059). Higher M-Tc levels separated A-B from A-L (AUC: 0.887; p < 0.0001). A linear regression model with prespecified clinical independent variables and neurofilament light chain plasma concentration showed that higher frequencies of LM-B predicted a shorter survival (hazard ratio: 1.094, CI: 1.026-1.167; p = 0.006). DISCUSSION: Our data suggest that a systemic elevation of senescent and late memory T and B lymphocytes is a feature of faster progressing ALS and of ALS individuals with bulbar involvement. Lymphocyte senescence and their memory state may be central to the immune dysregulation known to drive disease progression in ALS and a target for biomarkers and therapeutics discovery.
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Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/genética , Leucocitos Mononucleares , Estudios Retrospectivos , Progresión de la Enfermedad , Linfocitos T CD4-PositivosRESUMEN
The immune system protects from infections and cancer through complex cellular networks. For this purpose, immune cells require well-developed mechanisms of energy generation. However, the immune system itself can also cause diseases when defective regulation results in the emergence of autoreactive lymphocytes. Recent studies provide insights into how differential patterns of immune cell responses are associated with selective metabolic pathways. This review will examine the changing metabolic requirements of Th17 cells and of B cells at different stages of their development and activation. Both cells provide protection but can also mediate diseases through the production of autoantibodies and the production of proinflammatory mediators. In health, B cells produce antibodies and cytokines and present antigens to T cells to mount specific immunity. Th17 cells, on the other hand, provide protection against extra cellular pathogens at mucosal surfaces but can also drive chronic inflammation. The latter cells can also promote the differentiation of B cells to plasma cells to produce more autoantibodies. Metabolism-regulated checkpoints at different stages of their development ensure the that self-reactive B cells clones and needless production of interleukin (IL-)17 are limited. The metabolic regulation of the two cell types has some similarities, e.g. the utility of hypoxia induced factor (HIF)1α during low oxygen tension, to prevent autoimmunity and regulate inflammation. There are also clear differences, as Th17 cells only are vulnerable to the lack of certain amino acids. B cells, unlike Th17 cells, are also dependent of mechanistic target of rapamycin 2 (mTORC2) to function. Significant knowledge has recently been gained, particularly on Th17 cells, on how metabolism regulates these cells through influencing their epigenome. Metabolic dysregulation of Th17 cells and B cells can lead to chronic inflammation. Disease associated alterations in the genome can, in addition, cause dysregulation to metabolism and, thereby, result in epigenetic alterations in these cells. Recent studies highlight how pathology can result from the cooperation between the two cell types but only few have so far addressed the key metabolic alterations in such settings. Knowledge of the impact of metabolic dysfunction on chronic inflammation and pathology can reveal novel therapeutic targets to treat such diseases.
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Autoinmunidad , Células Th17 , Humanos , Linfocitos B , Inflamación , AutoanticuerposRESUMEN
Inflammation is well understood to be a physiological process of ageing however it also underlies many chronic diseases, including conditions without an obvious pathogenic inflammatory element. Recent findings have unequivocally identified type 2 diabetes (T2D) as a chronic inflammatory disease characterized by inflammation and immune senescence. Immunosenescence is a hallmark of the prolonged low-grade systemic inflammation, in particular associated with metabolic syndrome and can be a cause as well as a consequence of T2D. Diabetes is a risk factor for cardiovascular mortality and remodelling and with particular changes to myocardial structure, function, metabolism and energetics collectively resulting in diabetic cardiomyopathy. Both cardiomyocytes and immune cells undergo metabolic remodelling in T2D and as a result become trapped in a vicious cycle of lost metabolic flexibility, thus losing their key adaptive mechanisms to dynamic changes in O2 and nutrient availability. Immunosenescence driven by metabolic stress may be both the cause and key contributing factor to cardiac dysfunction in diabetic cardiomyopathy by inducing metabolic perturbations that can lead to impaired energetics, a strong predictor of cardiac mortality. Here we review our current understanding of the cross-talk between inflammaging and cardiomyocytes in T2D cardiomyopathy. We discuss potential mechanisms of metabolic convergence between cell types which, we hypothesize, might tip the balance between resolution of the inflammation versus adverse cardiac metabolic remodelling in T2D cardiomyopathy. A better understanding of the multiple biological paradigms leading to T2D cardiomyopathy including the immunosenescence associated with inflammaging will provide a powerful target for successful therapeutic interventions.
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GATA3 is as a lineage-specific transcription factor that drives the differentiation of CD4+ T helper 2 (Th2) cells, but is also involved in a variety of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages. Here we show a mechanism utilised by CD4+ T cells to increase mitochondrial mass in response to DNA damage through the actions of GATA3 and AMPK. Activated AMPK increases expression of PPARG coactivator 1 alpha (PPARGC1A or PGC1α protein) at the level of transcription and GATA3 at the level of translation, while DNA damage enhances expression of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). PGC1α, GATA3 and NRF2 complex together with the ATR to promote mitochondrial biogenesis. These findings extend the pleotropic interactions of GATA3 and highlight the potential for GATA3-targeted cell manipulation for intervention in CD4+ T cell viability and function after DNA damage.
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Linfocitos T CD4-Positivos/citología , Daño del ADN , Factor de Transcripción GATA3/metabolismo , Mitocondrias/metabolismo , Biogénesis de Organelos , Proteínas Quinasas Activadas por AMP/metabolismo , Adulto , Linfocitos T CD4-Positivos/metabolismo , Supervivencia Celular/genética , Células Cultivadas , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Humanos , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Cultivo Primario de CélulasAsunto(s)
Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , Hiperglucemia/diagnóstico , Enfermedad Aguda , Anciano , Glucemia/metabolismo , Péptido C/metabolismo , ChAdOx1 nCoV-19 , Comorbilidad , Urgencias Médicas , Humanos , Hiperglucemia/epidemiología , Hiperglucemia/metabolismo , Hipertensión/epidemiología , Masculino , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Estado Prediabético/epidemiología , SARS-CoV-2RESUMEN
BACKGROUND: In the general adult population, lymphopaenia is associated with an increased risk for hospitalisation with infection and infection-related death. The quality of evidence and strength of association between perioperative lymphopaenia across different surgical procedures and mortality/morbidity has not been examined by systematic review or meta-analysis. METHODS: We searched MEDLINE, Embase, Web of Science, Google Scholar, and Cochrane databases from their inception to June 29, 2020 for observational studies reporting lymphocyte count and in-hospital mortality rate in adults. We defined preoperative lymphopaenia as a lymphocyte count 1.0-1.5×109 L-1. Meta-analysis was performed using either fixed or random effects models. Quality was assessed using the Newcastle-Ottawa Scale. The I2 index was used to quantify heterogeneity. The primary outcome was in-hospital mortality rate and mortality rate at 30 days. RESULTS: Eight studies met the inclusion criteria for meta-analysis, comprising 4811 patients (age range, 46-91 yr; female, 20-79%). These studies examined preoperative lymphocyte count exclusively. Studies were of moderate to high quality overall, ranking >7 using the Newcastle-Ottawa Scale. Preoperative lymphopaenia was associated with a threefold increase in mortality rate (risk ratio [RR]=3.22; 95% confidence interval [CI], 2.19-4.72; P<0.01, I2=0%) and more frequent major postoperative complications (RR=1.33; 95% CI, 1.21-1.45; P<0.01, I2=6%), including cardiovascular morbidity (RR=1.77; 95% CI, 1.45-2.15; P<0.01, I2=0%), infections (RR=1.45; 95% CI, 1.19-1.76; P<0.01, I2=0%), and acute renal dysfunction (RR=2.66; 95% CI, 1.49-4.77; P<0.01, I2=1%). CONCLUSION: Preoperative lymphopaenia is associated with death and complications more frequently, independent of the type of surgery. PROSPERO REGISTRY NUMBER: CRD42020190702.
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Procedimientos Quirúrgicos Electivos/mortalidad , Mortalidad Hospitalaria , Linfopenia/mortalidad , Linfopenia/cirugía , Complicaciones Posoperatorias/mortalidad , Cuidados Preoperatorios/mortalidad , Procedimientos Quirúrgicos Electivos/efectos adversos , Procedimientos Quirúrgicos Electivos/tendencias , Mortalidad Hospitalaria/tendencias , Humanos , Morbilidad/tendencias , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Cuidados Preoperatorios/métodos , Cuidados Preoperatorios/tendencias , Estudios ProspectivosRESUMEN
Mitochondrial health and cellular metabolism can heavily influence the onset of senescence in T cells. CD8+ EMRA T cells exhibit mitochondrial dysfunction and alterations to oxidative phosphorylation, however, the metabolic properties of senescent CD8+ T cells from people living with type 2 diabetes (T2D) are not known. We show here that mitochondria from T2D CD8+ T cells had a higher oxidative capacity together with increased levels of mitochondrial reactive oxgen species (mtROS), compared to age-matched control cells. While fatty acid uptake was increased, fatty acid oxidation was impaired in T2D CD8+ EMRA T cells, which also showed an accumulation of lipid droplets and decreased AMPK activity. Increasing glucose and fatty acids in healthy CD8+ T cells resulted in increased p-p53 expression and a fragmented mitochondrial morphology, similar to that observed in T2D CD8+ EMRA T cells. The resulting mitochondrial changes are likely to have a profound effect on T cell function. Consequently, a better understanding of these metabolic abnormalities is crucial as metabolic manipulation of these cells may restore correct T cell function and help reduce the impact of T cell dysfunction in T2D.
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Chronic kidney disease (CKD) presents an ever-growing disease burden for the world's aging population. It is characterized by numerous changes to the kidney, including a decrease in renal mass, renal fibrosis, and a diminished glomerular filtration rate. The premature aging phenotype observed in CKD is associated with cellular senescence, particularly of renal tubular epithelial cells (TECs), which contributes to chronic inflammation through the production of a proinflammatory senescence associated secretory phenotype (SASP). When coupled with changes in immune system composition and progressive immune dysfunction, the accumulation of senescent kidney cells acts as a driver for the progression of CKD. The targeting of senescent cells may well present an attractive therapeutic avenue for the treatment of CKD. We propose that the targeting of senescent cells either by direct inhibition of pro-survival pathways (senolytics) or through the inhibition of their proinflammatory secretory profile (senomorphics) together with immunomodulation to enhance immune system surveillance of senescent cells could be of benefit to patients with CKD.
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We review here the seminal findings of Desdin-Mico et al. showing that T cells with dysfunctional mitochondria induce multimorbity and premature senescence, due to mitochondrial transcription factor A (TFAM). They add further weight to the idea that targeting immunometabolism could be beneficial in combating the detrimental effects of age-related disease.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Factores Inmunológicos/administración & dosificación , Interleucina-2/administración & dosificación , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27-CD28-CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27-CD28-CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27-CD28-CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.
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Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Senescencia Celular/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Citotoxicidad Inmunológica , Perfilación de la Expresión Génica , Humanos , Proteínas de la Membrana/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Proteínas Nucleares/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Células Asesinas Naturales/metabolismo , Transducción de Señal , Fiebre Amarilla/genética , Fiebre Amarilla/inmunología , Fiebre Amarilla/metabolismo , Fiebre Amarilla/virología , Virus de la Fiebre Amarilla/inmunologíaRESUMEN
The susceptibility of human CD4+ and CD8+ T cells to senesce differs, with CD8+ T cells acquiring an immunosenescent phenotype faster than the CD4+ T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4+ T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8+ T cells has knock-on consequences for nutrient usage, metabolism and function. Senescent CD4+ T cells uptake more lipid and glucose than their CD8+ counterparts, leading to a greater metabolic versatility engaging either an oxidative or a glycolytic metabolism. The enhanced metabolic advantage of senescent CD4+ T cells allows for more proliferation and migration than observed in the senescent CD8+ subset. Mitochondrial dysfunction has been linked to both cellular senescence and aging; however, it is still unclear whether mitochondria play a causal role in senescence. Our data show that reducing mitochondrial function in human CD4+ T cells, through the addition of low-dose rotenone, causes the generation of a CD4+ T cell with a CD8+ -like phenotype. Therefore, we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.
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Linfocitos T CD8-positivos/metabolismo , Senescencia Celular/inmunología , Inmunosenescencia/fisiología , Mitocondrias/metabolismo , Adenosina Trifosfato/metabolismo , Adulto , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Movimiento Celular/inmunología , Proliferación Celular/fisiología , Senescencia Celular/fisiología , Glucosa/metabolismo , Glucólisis/inmunología , Humanos , Antígenos Comunes de Leucocito/sangre , Antígenos Comunes de Leucocito/metabolismo , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Mitocondrias/fisiología , Mitocondrias/ultraestructura , Rotenona/farmacologíaRESUMEN
The skin is our interface with the outside world, and consequently it is exposed to a wide range of microbes and allergens. Recent studies have indicated that allergen-specific skin-resident memory T (TRM) cells play a role in allergic contact dermatitis (ACD). However, the composition and dynamics of the epidermal T-cell subsets during ACD are not known. Here we show that exposure of the skin to the experimental contact allergen DNFB results in a displacement of the normally occurring dendritic epidermal T cells (DETC) concomitant with an accumulation of epidermal CD8+CD69+CD103+ TRM cells in mice. By studying knockout mice, we provide evidence that CD8+ T cells are required for the displacement of the DETC and that DETC are not required for recruitment of CD8+ TRM cells to the epidermis following allergen exposure. We demonstrate that the magnitude of the allergic reaction correlates with the number of CD8+ epidermal TRM cells, which again correlates with allergen dose and number of allergen exposures. Finally, in an attempt to elucidate why CD8+ epidermal TRM cells persist in the epidermis, we show that CD8+ epidermal TRM cells have a higher proliferative capability and are bioenergetically more stable, displaying a higher spare respiratory capacity than DETC.
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Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Dermatitis Alérgica por Contacto/inmunología , Memoria Inmunológica , Animales , Linfocitos T CD8-positivos/patología , Células Dendríticas/patología , Dermatitis Alérgica por Contacto/patología , Modelos Animales de Enfermedad , Epidermis/patología , Ratones , Ratones NoqueadosRESUMEN
The impact of cellular senescence during ageing is well established, however senescence is now recognised to play a role in a variety of age related and metabolic diseases, such as cancer, autoimmune and cardiovascular diseases. It is therefore crucial to gain a better understanding of the mechanisms that control cellular senescence. In recent years our understanding of the intimate relationship between cell metabolism, cell signalling and cellular senescence has greatly improved. In this review we discuss the differing roles of glucose and protein metabolism in both senescent fibroblast and CD8+ T-cells, and explore the impact cellular metabolism has on the senescence-associated secretory phenotype (SASP) of these cell types.
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Linfocitos T CD8-positivos/metabolismo , Senescencia Celular/fisiología , Fibroblastos/metabolismo , Animales , Linfocitos T CD8-positivos/patología , Fibroblastos/patología , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Transducción de Señal/fisiología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
Cellular senescence is accompanied by a senescence-associated secretory phenotype (SASP). We show here that primary human senescent CD8+ T cells also display a SASP comprising chemokines, cytokines and extracellular matrix remodelling proteases that are unique to this subset and contribute to age-associated inflammation. We found the CD8+ CD45RA+ CD27- EMRA subset to be the most heterogeneous, with a population aligning with the naïve T cells and another with a closer association to the effector memory subset. However, despite the differing processes that give rise to these senescent CD8+ T cells once generated, they both adopt a unique secretory profile with no commonality to any other subset, aligning more closely with senescence than quiescence. Furthermore, we also show that the SASP observed in senescent CD8+ T cells is governed by p38 MAPK signalling.