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While some people pore over the textbook and train through the classics of the field, many scientists come to immunology when they discover it intersecting with their "first love" interests. Five of these "accidental immunologists" tell us how they found their way to a fascination with the immune system.
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Alergia e Imunologia , Humanos , História do Século XX , História do Século XXI , Animais , Sistema ImunitárioRESUMO
The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.
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Tecido Adiposo , Obesidade , Homeostase , Humanos , Obesidade/genéticaRESUMO
Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor-positive (LepR+) sympathetic perineurial barrier cells (SPCs) present in mice and humans, which uniquely co-express Lepr and interleukin-33 (Il33) and ensheath AT sympathetic axon bundles. Brown ATs (BATs) of mice lacking IL-33 in SPCs (SPCΔIl33) had fewer regulatory T (Treg) cells and eosinophils, resulting in increased BAT inflammation. SPCΔIl33 mice were more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCΔIl33 mice had impaired adaptive thermogenesis and were unresponsive to leptin-induced rescue of metabolic adaptation. We therefore identify LepR+ SPCs as a source of IL-33, which orchestrate an anti-inflammatory BAT environment, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL-33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.
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Tecido Adiposo Marrom , Leptina , Animais , Humanos , Camundongos , Tecido Adiposo Marrom/inervação , Tecido Adiposo Marrom/metabolismo , Peso Corporal , Metabolismo Energético/fisiologia , Interleucina-33/genética , Interleucina-33/metabolismo , Obesidade/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Termogênese/fisiologiaRESUMO
Fasting is known to impact monocyte dynamics and phenotype, but the mechanics and functional significance of this response remain unclear. In this issue of Immunity, Janssen and colleagues demonstrate that fasting and re-feeding causes monocytes to re-enter the bone marrow and alter the host response to infection.
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Medula Óssea , Monócitos , Células da Medula ÓsseaRESUMO
Leptin is a hormone produced by the adipose tissue that acts in the brain, stimulating white fat breakdown. We find that the lipolytic effect of leptin is mediated through the action of sympathetic nerve fibers that innervate the adipose tissue. Using intravital two-photon microscopy, we observe that sympathetic nerve fibers establish neuro-adipose junctions, directly "enveloping" adipocytes. Local optogenetic stimulation of sympathetic inputs induces a local lipolytic response and depletion of white adipose mass. Conversely, genetic ablation of sympathetic inputs onto fat pads blocks leptin-stimulated phosphorylation of hormone-sensitive lipase and consequent lipolysis, as do knockouts of dopamine ß-hydroxylase, an enzyme required for catecholamine synthesis. Thus, neuro-adipose junctions are necessary and sufficient for the induction of lipolysis in white adipose tissue and are an efferent effector of leptin action. Direct activation of sympathetic inputs to adipose tissues may represent an alternative approach to induce fat loss, circumventing central leptin resistance. PAPERCLIP.
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Tecido Adiposo Branco/metabolismo , Leptina/metabolismo , Lipólise , Tecido Adiposo Branco/inervação , Animais , Humanos , Camundongos , Fosforilação , Receptores Adrenérgicos beta/metabolismo , Sistema Nervoso Simpático/metabolismoRESUMO
RORγt(+) Th17 cells are important for mucosal defenses but also contribute to autoimmune disease. They accumulate in the intestine in response to microbiota and produce IL-17 cytokines. Segmented filamentous bacteria (SFB) are Th17-inducing commensals that potentiate autoimmunity in mice. RORγt(+) T cells were induced in mesenteric lymph nodes early after SFB colonization and distributed across different segments of the gastrointestinal tract. However, robust IL-17A production was restricted to the ileum, where SFB makes direct contact with the epithelium and induces serum amyloid A proteins 1 and 2 (SAA1/2), which promote local IL-17A expression in RORγt(+) T cells. We identified an SFB-dependent role of type 3 innate lymphoid cells (ILC3), which secreted IL-22 that induced epithelial SAA production in a Stat3-dependent manner. This highlights the critical role of tissue microenvironment in activating effector functions of committed Th17 cells, which may have important implications for how these cells contribute to inflammatory disease.
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Microbioma Gastrointestinal , Interleucinas/metabolismo , Intestinos/imunologia , Receptores de Interleucina/metabolismo , Proteína Amiloide A Sérica/metabolismo , Células Th17/imunologia , Animais , Imunidade Inata , Interleucinas/imunologia , Intestinos/anatomia & histologia , Intestinos/microbiologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina/imunologia , Transdução de Sinais , Interleucina 22RESUMO
Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns1. Here we uncover the mechanism by which NPY in sympathetic neurons2,3 protects from obesity. Imaging of cleared mouse brown and white adipose tissue (BAT and WAT, respectively) established that NPY+ sympathetic axons are a smaller subset that mostly maps to the perivasculature; analysis of single-cell RNA sequencing datasets identified mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains the proliferation of mural cells, which are a source of thermogenic adipocytes in both BAT and WAT4-6. We found that diet-induced obesity leads to neuropathy of NPY+ axons and concomitant depletion of mural cells. This defect was replicated in mice with NPY abrogated from sympathetic neurons. The loss of NPY in sympathetic neurons whitened interscapular BAT, reducing its thermogenic ability and decreasing energy expenditure before the onset of obesity. It also caused adult-onset obesity of mice fed on a regular chow diet and rendered them more susceptible to diet-induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.
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The hypothalamic-pituitary-adrenal axis modulates immunity in response to stress. In a recent report in the May 14, 2020 issue of Nature, Zhang et al. use optogenetic tools to investigate whether the splenic immune response is directly controlled by descending neuronal circuits activated in response to stress.
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Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Encéfalo , Imunidade Humoral , NeurôniosRESUMO
Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as important regulators of host defence and inflammation1-4. Nevertheless, it is unclear whether neuronal and immune cells co-operate in brain-body axes to orchestrate metabolism and obesity. Here we describe a neuro-mesenchymal unit that controls group 2 innate lymphoid cells (ILC2s), adipose tissue physiology, metabolism and obesity via a brain-adipose circuit. We found that sympathetic nerve terminals act on neighbouring adipose mesenchymal cells via the ß2-adrenergic receptor to control the expression of glial-derived neurotrophic factor (GDNF) and the activity of ILC2s in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to alterations in ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing and chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates ILC2s in gonadal fat and connects to higher-order brain areas, including the paraventricular nucleus of the hypothalamus. Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity.
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Tecido Adiposo/inervação , Tecido Adiposo/metabolismo , Encéfalo/metabolismo , Imunidade Inata/imunologia , Mesoderma/citologia , Vias Neurais , Neurônios/citologia , Obesidade/metabolismo , Tecido Adiposo/citologia , Animais , Encéfalo/citologia , Sinais (Psicologia) , Citocinas/metabolismo , Metabolismo Energético , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Gônadas/metabolismo , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Sistema Nervoso Simpático/citologia , Sistema Nervoso Simpático/metabolismoRESUMO
Change History: This Article has been retracted; see accompanying Retraction. Corrected online 20 January: In this Article, author Frank Rigo was incorrectly listed with a middle initial; this has been corrected in the online versions of the paper.
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T helper 17 (TH17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORγt partner that coordinates transcription of selective TH17 genes, and is required for TH17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5-RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in TH17-dependent diseases.
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RNA Helicases DEAD-box/metabolismo , RNA Longo não Codificante/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Animais , Cromatina/genética , Cromatina/metabolismo , RNA Helicases DEAD-box/genética , Feminino , Regulação da Expressão Gênica/genética , Cabelo/anormalidades , Doença de Hirschsprung/genética , Humanos , Síndromes de Imunodeficiência/genética , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Especificidade de Órgãos , Osteocondrodisplasias/congênito , Osteocondrodisplasias/genética , Doenças da Imunodeficiência Primária , Ligação Proteica , RNA Longo não Codificante/genética , Transcrição Gênica/genéticaRESUMO
Obesity is a worldwide public health concern yet no safe therapies are currently available. The activity of sympathetic neurons is necessary and sufficient for fat mass reduction, via norepinephrine (NE) signaling. Macrophage accumulation in the adipose tissue is thought to play the central role in the onset of obesity, yet their relation to NE has been controversial. We have identified a population of sympathetic neuron-associated macrophages (SAMs) that control obesity via the uptake and clearing of NE. Here we focus on the neuro-immune regulation of obesity by discussing the genetic, cellular and functional signatures of SAMs vis-a-vis adipose tissue macrophages (ATMs).
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Tecido Adiposo/imunologia , Macrófagos/imunologia , Neurônios/imunologia , Obesidade/imunologia , Sistema Nervoso Simpático/imunologia , Adipócitos/imunologia , Tecido Adiposo/inervação , Animais , Homeostase/imunologia , Humanos , Norepinefrina/imunologia , Norepinefrina/metabolismo , Obesidade/fisiopatologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
In recent decades, obesity has become a global public health crisis irrespective of age or gender [20]. But according to historic records, concerns over appropriate maintenance of body size have been long established. For more than to 2 millennia, the main therapeutic approach to curb excess weight has been to recommend dietary restrictions and regular exercise (Haslam, 2016). Nevertheless, more contemporary studies indicate that the employment of such approaches in the treatment of severely obese patients causes metabolic adaptions which impair their long-term success in weight management [8]. These evidences highlight thus, the urgency in the search for a more comprehensive knowledge of the mechanisms that underlie the control of body weight, which would be essential for the development of effective strategies for the treatment of obesity and its comorbidities. Importantly, the discovery of the hormone leptin [33]and the use of novel techniques in targeted transgenesis [32] have enabled progress in defining some of the key players and the molecular mechanisms that are involved in the processes that control body size homeostasis and energy balance, and how obesity may disrupt leptin's feedback loop and lead to the pathology of metabolic syndrome. On the light of such findings, here we review how the sympathetic nervous system modulates adipose tissue metabolism downstream of leptin's action on the CNS, with particular focus on how this system may be disrupted in the context of excess adiposity, plus highlight the potential clinical implications arising from a better understanding of the physiologic control of the sympathetic neuro-adipose connection.
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Tecido Adiposo/fisiologia , Peso Corporal , Metabolismo Energético , Sistema Nervoso Simpático/fisiologia , Animais , HumanosRESUMO
The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (LepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted LepR in T cells. In contrast with pleiotropic immune disorders reported in obese mice with leptin or LepR deficiency, we found that LepR deficiency in CD4(+) T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation toward a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the STAT3 and its downstream targets. This study establishes cell-intrinsic roles for LepR signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function.
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Diferenciação Celular/imunologia , Leptina/imunologia , Obesidade/imunologia , Receptores para Leptina/imunologia , Células Th17/citologia , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Diferenciação Celular/genética , Células Cultivadas , Citrobacter rodentium/imunologia , Colite/imunologia , Infecções por Enterobacteriaceae/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Receptores para Leptina/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células Th17/imunologiaRESUMO
People think they are in control of their own decisions: what to eat or drink, whom to marry or pick a fight with, where to live, what to buy. Behavioural economists and neurophysiologists have long studied decision-making behaviours. However, these behaviours have only recently been studied through the light of molecular genetics. Here, we review recent research in mice, Drosophila melanogaster and Caenorhabditis elegans, that analyses the molecular and cellular mechanisms underlying decision-making. These studies interrogate decision-making about food, sexual behaviour, aggression or foraging strategies, and add molecular and cell biology understanding onto the consilience of brain and decision.