RESUMEN
Ketone bodies are short-chain fatty acids produced by the liver during periods of limited glucose availability, such as during fasting or low carbohydrate feeding. Recent studies have highlighted important nonmetabolic functions of the most abundant ketone body, ß-hydroxybutyrate (BHB). Notably, many of these functions, including limiting specific sources of inflammation, histone deacetylase inhibition, NFκB inhibition, and GPCR stimulation, are particularly important to consider in immune cells. Likewise, dietary manipulations like caloric restriction or ketogenic diet feeding have been associated with lowered inflammation, improved health outcomes, and improved host defense against infection. However, the underlying mechanisms of the broad benefits of ketosis remain incompletely understood. In this Perspective, we contextualize the current state of the field of nonmetabolic functions of ketone bodies specifically in the immune system and speculate on the molecular explanations and broader physiological significance.
Asunto(s)
Cuerpos Cetónicos , Cetosis , Humanos , Ácido 3-Hidroxibutírico , Sistema Inmunológico , InflamaciónRESUMEN
Aging is accompanied by chronic low-grade inflammation, but the mechanisms that allow this to persist are not well understood. Ketone bodies are alternative fuels produced when glucose is limited and improve indicators of healthspan in aging mouse models. Moreover, the most abundant ketone body, ß-hydroxybutyrate, inhibits the NLRP3 inflammasome in myeloid cells, a key potentiator of age-related inflammation. Given that myeloid cells express ketogenic machinery, we hypothesized this pathway may serve as a metabolic checkpoint of inflammation. To test this hypothesis, we conditionally ablated ketogenesis by disrupting expression of the terminal enzyme required for ketogenesis, 3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL). By deleting HMGCL in the liver, we validated the functional targeting and establish that the liver is the only organ that can produce the life-sustaining quantities of ketone bodies required for survival during fasting or ketogenic diet feeding. Conditional ablation of HMGCL in neutrophils and macrophages had modest effects on body weight and glucose tolerance in aging but worsened glucose homeostasis in myeloid cell-specific Hmgcl-deficient mice fed a high-fat diet. Our results suggest that during aging, liver-derived circulating ketone bodies might be more important for deactivating the NLRP3 inflammasome and controlling organismal metabolism.
Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Ratones , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Cuerpos Cetónicos , Inflamación/genética , Glucosa/metabolismo , Inmunidad InnataRESUMEN
Cholesterol biosynthetic intermediates, such as lanosterol and desmosterol, are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here, we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3ß-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single-cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon responses and attenuates the expression of antiinflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/retinoid X receptor (RXR) activation and thus macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mitochondrial reactive oxygen species production and NLR family pyrin domain containing 3 (NLRP3)-dependent inflammasome activation. Deficiency of NLRP3 or apoptosis-associated speck-like protein containing a CARD (ASC) rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation by integrating with macrophage cholesterol metabolism and inflammatory activation and protecting from disease progression.
Asunto(s)
Aterosclerosis/tratamiento farmacológico , Desmosterol/farmacología , Inflamasomas/metabolismo , Inflamación/tratamiento farmacológico , Activación de Macrófagos/efectos de los fármacos , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Colesterol/metabolismo , Vasos Coronarios , Células Espumosas/metabolismo , Humanos , Inflamación/metabolismo , Metabolismo de los Lípidos , Receptores X del Hígado/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Placa Aterosclerótica/metabolismo , Esteroles/metabolismoRESUMEN
Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides, declines with age. The defect in the mobilization of free fatty acids in the elderly is accompanied by increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. Although catecholamine signalling in adipocytes is normal in the elderly, how lipolysis is impaired in ageing remains unknown. Here we show that adipose tissue macrophages regulate the age-related reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased whole-transcriptome analyses of adipose macrophages revealed that ageing upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in ageing restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3) and monoamine oxidase A (MAOA) that is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1. Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-immunometabolic signalling between the sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.
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Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Envejecimiento/metabolismo , Catecolaminas/metabolismo , Inflamasomas/metabolismo , Lipólisis , Macrófagos/metabolismo , Tejido Adiposo/citología , Tejido Adiposo/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Animales , Caspasa 1/metabolismo , Catecolaminas/farmacología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Factor 3 de Diferenciación de Crecimiento/deficiencia , Factor 3 de Diferenciación de Crecimiento/genética , Factor 3 de Diferenciación de Crecimiento/metabolismo , Lipasa/metabolismo , Lipólisis/efectos de los fármacos , Lipólisis/genética , Ratones , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Norepinefrina/metabolismo , Esterol Esterasa/metabolismoRESUMEN
KEY POINTS: Oestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies. Insulin sensitivity is greater in premenopausal women compared with age-matched men, and metabolism-related cardiovascular diseases and type 2 diabetes are less frequent in these same women. Both female and male mice treated with oestradiol are protected against obesity-induced insulin resistance. The protection against obesity-induced insulin resistance is associated with reduced ectopic lipid content in liver and skeletal muscle. These results were associated with increased insulin-stimulated suppression of white adipose tissue lipolysis and reduced inflammation. ABSTRACT: Oestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies. Overall, females are protected against obesity-induced insulin resistance; yet, the mechanisms responsible for this protection are not well understood. Therefore, the aim of the present work was to evaluate the underlying mechanism(s) by which female mice are protected against obesity-induced insulin resistance compared with male mice. We studied male and female mice in age-matched or body weight-matched conditions. They were fed a high-fat diet (HFD) or regular chow for 4 weeks. We also studied HFD male mice treated with oestradiol or vehicle. Both HFD female and HFD male mice treated with oestradiol displayed increased whole-body insulin sensitivity, associated with reduction in ectopic hepatic and muscle lipid content compared to HFD male mice. Reductions in ectopic lipid content in these mice were associated with increased insulin-stimulated suppression of white adipose tissue (WAT) lipolysis. Both HFD female and HFD male mice treated with oestradiol also displayed striking reductions in WAT inflammation, represented by reductions in plasma and adipose tissue tumour necrosis factor α and interleukin 6 concentrations. Taken together these data support the hypothesis that HFD female mice are protected from obesity-induced insulin resistance due to oestradiol-mediated reductions in WAT inflammation, leading to improved insulin-mediated suppression of WAT lipolysis and reduced ectopic lipid content in liver and skeletal muscle.
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Estrógenos/farmacología , Resistencia a la Insulina , Interleucina-6/metabolismo , Caracteres Sexuales , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Peso Corporal , Línea Celular , Células Cultivadas , Dieta Alta en Grasa/efectos adversos , Estrógenos/metabolismo , Femenino , Lipólisis , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Aging is the greatest risk factor for the development of chronic diseases such as arthritis, type 2 diabetes, cardiovascular disease, kidney disease, Alzheimer's disease, macular degeneration, frailty, and certain forms of cancers. It is widely regarded that chronic inflammation may be a common link in all these age-related diseases. This raises the question, can one alter the course of aging and potentially slow the development of all chronic diseases by manipulating the mechanisms that cause age-related inflammation? Emerging evidence suggests that pro-inflammatory cytokines interleukin-1 (IL-1) and IL-18 show an age-dependent regulation implicating inflammasome-mediated caspase-1 activation in the aging process. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome controls the caspase-1 activation in myeloid-lineage cells in several organs during aging. The NLRP3 inflammasome is especially relevant to aging as it can get activated in response to structurally diverse damage-associated molecular patterns (DAMPs) such as extracellular ATP, excess glucose, ceramides, amyloids, urate, and cholesterol crystals, all of which increase with age. Interestingly, reduction in NLRP3-mediated inflammation prevents age-related insulin resistance, bone loss, cognitive decline, and frailty. NLRP3 is a major driver of age-related inflammation and therefore dietary or pharmacological approaches to lower aberrant inflammasome activation holds promise in reducing multiple chronic diseases of age and may enhance healthspan.
Asunto(s)
Envejecimiento/inmunología , Proteínas Portadoras/metabolismo , Inflamación/inmunología , Células Mieloides/inmunología , Animales , Proteínas Portadoras/inmunología , Caspasa 1/metabolismo , Humanos , Interleucina-1/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLRRESUMEN
Direct mammalian target of rapamycin (Rapa) complex 1 inhibition by short-term low-dose Rapa treatment has recently been shown to improve CD8 T cell immunological memory. Whereas these studies focused on memory development, the impact of low-dose Rapa on the primary immune response, particularly as it relates to functional effector immunity, is far less clear. In this study, we investigated the impact of acute Rapa treatment on immune effector cell function during the primary immune response to several acute infections. We found that functional CD8 T cell and macrophage responses to both viral and intracellular bacterial pathogens were depressed in mice in vivo and in humans to phorbol ester and calcium ionophore stimulation in vitro in the face of low-dose Rapa treatment. Mechanistically, the CD8 defect was linked to impaired glycolytic switch in stimulated naive cells and the reduced formation of short-lived effector cells. Therefore, more than one cell type required for a protective effector immune response is impaired by Rapa in both mice and humans, at the dose shown to improve immune memory and extend lifespan. This urges caution with regard to the relative therapeutic costs and benefits of Rapa treatment as means to improve immune memory.
Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Sirolimus/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos , Adulto , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Glucólisis/efectos de los fármacos , Glucólisis/inmunología , Granzimas/inmunología , Granzimas/metabolismo , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Humanos , Concentración de Iones de Hidrógeno , Memoria Inmunológica/inmunología , Inmunosupresores/farmacología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Listeria monocytogenes/efectos de los fármacos , Listeria monocytogenes/inmunología , Listeria monocytogenes/fisiología , Listeriosis/inmunología , Listeriosis/microbiología , Listeriosis/prevención & control , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/prevención & control , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/efectos de los fármacos , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Lisosomas/química , Lisosomas/efectos de los fármacos , Lisosomas/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Microbial infection during various stages of human development produces widely different clinical outcomes, yet the links between age-related changes in the immune compartment and functional immunity remain unclear. The ability of the immune system to respond to specific antigens and mediate protection in early life is closely correlated with the level of diversification of lymphocyte antigen receptors. We have previously shown that the neonatal primary CD8+ T cell response to replication competent virus is significantly constricted compared to the adult response. In the present study, we have analyzed the subsequent formation of neonatal memory CD8+ T cells and their response to secondary infectious challenge. In particular, we asked whether the less diverse CD8+ T cell clonotypes that are elicited by neonatal vaccination with replication competent virus are 'locked-in' to the adult memory T cell, and thus may compromise the strength of adult immunity. Here we report that neonatal memory CD8+ T cells mediate poor recall responses compared to adults and are comprised of a repertoire of lower avidity T cells. During a later infectious challenge the neonatal memory CD8+ T cells compete poorly with the fully diverse repertoire of naïve adult CD8+ T cells and are outgrown by the adult primary response. This has important implications for the timing of vaccination in early life.
Asunto(s)
Envejecimiento , Linfocitos T CD8-positivos/inmunología , Síndromes de Inmunodeficiencia/etiología , Memoria Inmunológica , Listeriosis/fisiopatología , Modelos Inmunológicos , Vacunas Atenuadas/inmunología , Animales , Animales Recién Nacidos , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , ADN Recombinante/metabolismo , Herpes Simple/inmunología , Herpes Simple/prevención & control , Herpes Simple/virología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/metabolismo , Sistema Inmunológico/crecimiento & desarrollo , Sistema Inmunológico/inmunología , Sistema Inmunológico/patología , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/metabolismo , Síndromes de Inmunodeficiencia/patología , Listeria monocytogenes/genética , Listeria monocytogenes/inmunología , Listeria monocytogenes/metabolismo , Listeria monocytogenes/patogenicidad , Listeriosis/inmunología , Listeriosis/microbiología , Listeriosis/prevención & control , Ratones Endogámicos , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Organismos Libres de Patógenos Específicos , Vacunas Atenuadas/efectos adversos , Vaccinia/inmunología , Vaccinia/prevención & control , Vaccinia/virología , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Virus Vaccinia/metabolismo , VirulenciaRESUMEN
Ketone bodies are short-chain fatty acids produced in the liver during periods of limited glucose availability that provide an alternative energy source for the brain, heart, and skeletal muscle. Beyond this metabolic role, ß-hydroxybutyrate (BHB), is gaining recognition as a signaling molecule. Lysine ß-hydroxybutyrylation (Kbhb) is a newly discovered post-translational modification in which BHB is covalently attached to lysine ε-amino groups. This protein adduct is metabolically sensitive, dependent on BHB concentration, and found on proteins in multiple intracellular compartments. Therefore, Kbhb is hypothesized to be an important component of ketone body-regulated physiology. Kbhb on histones is proposed to be an epigenetic regulator, which links metabolic alterations to gene expression. However, we found that the widely used antibody against ß-hydroxybutyrylated lysine 9 on histone H3 (H3K9bhb) also recognizes other modification(s) that likely include acetylation. Therefore, caution must be used when interpreting gene regulation data acquired with the H3K9bhb antibody.
RESUMEN
Starvation and low carbohydrate diets lead to the accumulation of the ketone body, ß-hydroxybutyrate (BHB), whose blood concentrations increase more than 10-fold into the millimolar range. In addition to providing a carbon source, BHB accumulation triggers lysine ß-hydroxybutyrylation (Kbhb) of proteins via unknown mechanisms. As with other lysine acylation events, Kbhb marks can be removed by histone deacetylases (HDACs). Here, we report that class I HDACs unexpectedly catalyze protein lysine modification with ß-hydroxybutyrate (BHB). Mutational analyses of the HDAC2 active site reveal a shared reliance on key amino acids for classical deacetylation and non-canonical HDAC-catalyzed ß-hydroxybutyrylation. Also consistent with reverse HDAC activity, Kbhb formation is driven by mass action and substrate availability. This reverse HDAC activity is not limited to BHB but also extends to multiple short-chain fatty acids. The reversible activity of class I HDACs described here represents a novel mechanism of PTM deposition relevant to metabolically-sensitive proteome modifications.
RESUMEN
Aging impairs the integrated immunometabolic responses, which have evolved to maintain core body temperature in homeotherms to survive cold stress, infections, and dietary restriction. Adipose tissue inflammation regulates the thermogenic stress response, but how adipose tissue-resident cells instigate thermogenic failure in the aged are unknown. Here, we define alterations in the adipose-resident immune system and identify that type 2 innate lymphoid cells (ILC2s) are lost in aging. Restoration of ILC2 numbers in aged mice to levels seen in adults through IL-33 supplementation failed to rescue old mice from metabolic impairment and increased cold-induced lethality. Transcriptomic analyses revealed intrinsic defects in aged ILC2, and adoptive transfer of adult ILC2s are sufficient to protect old mice against cold. Thus, the functional defects in adipose ILC2s during aging drive thermogenic failure.
Asunto(s)
Inmunidad Innata , Interleucina-33 , Tejido Adiposo , Envejecimiento , Animales , Pulmón , Linfocitos , Ratones , Ratones Endogámicos C57BLRESUMEN
Inflammation is a broad term that refers to a collection of carefully balanced programs in the body. These pathways are essential for detecting invading microorganisms, controlling the spread of infection, and instructing appropriate immune responses to eliminate pathogens. During aging there is deterioration of important regulatory mechanisms, giving rise to persistent low-grade inflammation that drives chronic conditions such as metabolic dysregulation, immune senescence, and cognitive decline. Understanding this aspect of the pathobiology of aging is key to uncovering the source(s) and cause(s) of age-related inflammation that underlies disease.
RESUMEN
The collective loss of immune protection during aging leads to poor vaccine responses and an increased severity of infection for the elderly. Here, we review our current understanding of effects of aging on the cellular and molecular dysregulation of innate immune cells as well as the relevant tissue milieu which influences their functions. The innate immune system is composed of multiple cell types which provide distinct and essential roles in tissue surveillance and antigen presentation as well as early responses to infection or injury. Functional defects that arise during aging lead to a reduced dynamic range of responsiveness, altered cytokine dynamics, and impaired tissue repair. Heightened inflammation influences both the dysregulation of innate immune responses as well as surrounding tissue microenvironments which have a critical role in development of a functional immune response. In particular, age-related physical and inflammatory changes in the skin, lung, lymph nodes, and adipose tissue reflect disrupted architecture and spatial organization contributing to diminished immune responsiveness. Underlying mechanisms include altered transcriptional programming and dysregulation of critical innate immune signaling cascades. Further, we identify signaling functions of bioactive lipid mediators which address chronic inflammation and may contribute to the resolution of inflammation to improve innate immunity during aging.
Asunto(s)
Envejecimiento/inmunología , Inmunidad Innata/fisiología , Inflamación/inmunología , Anciano , Humanos , Pulmón/inmunología , Ganglios Linfáticos/inmunología , Piel/inmunología , VacunaciónRESUMEN
Ketone bodies are essential alternative fuels that allow humans to survive periods of glucose scarcity induced by starvation and prolonged exercise. A widely used ketogenic diet (KD), which is extremely high in fat with very low carbohydrates, drives the host into using ß-hydroxybutyrate for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis affects adipose tissue to control inflammation and energy homeostasis. Here, by using single-cell RNA sequencing of adipose-tissue-resident immune cells, we show that KD expands metabolically protective γδ T cells that restrain inflammation. Notably, long-term ad libitum KD feeding in mice causes obesity, impairs metabolic health and depletes the adipose-resident γδ T cells. In addition, mice lacking γδ T cells have impaired glucose homeostasis. Our results suggest that γδ T cells are mediators of protective immunometabolic responses that link fatty acid-driven fuel use to reduced adipose tissue inflammation.
Asunto(s)
Grasa Intraabdominal/metabolismo , Cuerpos Cetónicos/biosíntesis , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Animales , Glucemia/metabolismo , Dieta Cetogénica , Homeostasis , Inflamación/metabolismo , Grasa Intraabdominal/inmunología , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Linfocitos T/inmunologíaRESUMEN
Respiratory viral infections remain a scourge, with seasonal influenza infecting millions and killing many thousands annually and viral pandemics, such as COVID-19, recurring every decade. Age, cardiovascular disease, and diabetes mellitus are risk factors for severe disease and death from viral infection. Immunometabolic therapies for these populations hold promise to reduce the risks of death and disability. Such interventions have pleiotropic effects that might not only target the virus itself but also enhance supportive care to reduce cardiopulmonary complications, improve cognitive resilience, and facilitate functional recovery. Ketone bodies are endogenous metabolites that maintain cellular energy but also feature drug-like signaling activities that affect immune activity, metabolism, and epigenetics. Here, we provide an overview of ketone body biology relevant to respiratory viral infection, focusing on influenza A and severe acute respiratory syndrome (SARS)-CoV-2, and discuss the opportunities, risks, and research gaps in the study of exogenous ketone bodies as novel immunometabolic interventions in these diseases.
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COVID-19 , Gripe Humana , Humanos , Gripe Humana/prevención & control , Cuerpos Cetónicos , Pandemias/prevención & control , SARS-CoV-2RESUMEN
An integrated immunometabolic response during negative energy balance is required for host survival. Three new papers by Jordan et al. (2019), Nagai et al. (2019), and Collins et al. (2019) report that monocytes, naive B cells, and memory CD8 T cells use bone marrow as a haven to tide off periods of metabolic adversity to maintain immune-responsiveness.
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Médula Ósea , Inmunidad Mucosa , Células de la Médula Ósea , Ayuno , Monocitos , Linfocitos TRESUMEN
Influenza A virus (IAV) infection-associated morbidity and mortality are a key global health care concern, necessitating the identification of new therapies capable of reducing the severity of IAV infections. In this study, we show that the consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. KD feeding resulted in an expansion of γδ T cells in the lung that improved barrier functions, thereby enhancing antiviral resistance. Expansion of these protective γδ T cells required metabolic adaptation to a ketogenic diet because neither feeding mice a high-fat, high-carbohydrate diet nor providing chemical ketone body substrate that bypasses hepatic ketogenesis protected against infection. Therefore, KD-mediated immune-metabolic integration represents a viable avenue toward preventing or alleviating influenza disease.
Asunto(s)
Dieta Cetogénica , Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/inmunología , Linfocitos T/inmunología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/virologíaRESUMEN
During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT.
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Tejido Adiposo , Envejecimiento/metabolismo , Linfocitos B , Homeostasis , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Regulación de la Temperatura Corporal , Respuesta al Choque por Frío , Femenino , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Lipólisis , Masculino , Ratones , Receptores de Interleucina-1/metabolismoRESUMEN
OBJECTIVE: Fatty acid oxidation in macrophages is thought to regulate inflammatory status and insulin-sensitivity. An important unanswered question in this field is whether carnitine acetyl-transferase (CrAT) that regulates fatty acid oxidation and mitochondrial acetyl-CoA balance is required to integrate nutrient stress sensing to inflammatory response in macrophages. METHODS: Mice with myeloid lineage-specific Crat deletion were subjected to several metabolic stressors, including high-fat diet-induced obesity, fasting, and LPS-induced endotoxemia. Their metabolic homeostasis was compared to that of Crat-sufficient littermate controls. Inflammatory potential of Crat-deficient and Crat-sufficient macrophages were measured both in vitro and in vivo. RESULTS: Our studies revealed that ablation of CrAT in myeloid lineage cells did not impact glucose homeostasis, insulin-action, adipose tissue leukocytosis, and inflammation when animals were confronted with a variety of metabolic stressors, including high-fat diet, fasting, or LPS-induced acute endotoxemia. CONCLUSIONS: These findings demonstrate that unlike muscle cells, substrate switch mechanisms that control macrophage energy metabolism and mitochondrial short-chain acyl-CoA pools during nutrient stress are controlled by pathways that are not solely reliant on CrAT.