RESUMO
Sustained responses to transient environmental stimuli are important for survival. The mechanisms underlying long-term adaptations to temporary shifts in abiotic factors remain incompletely understood. Here, we find that transient cold exposure leads to sustained transcriptional and metabolic adaptations in brown adipose tissue, which improve thermogenic responses to secondary cold encounter. Primary thermogenic challenge triggers the delayed induction of a lipid biosynthesis programme even after cessation of the original stimulus, which protects from subsequent exposures. Single-nucleus RNA sequencing and spatial transcriptomics reveal that this response is driven by a lipogenic subpopulation of brown adipocytes localized along the perimeter of Ucp1hi adipocytes. This lipogenic programme is associated with the production of acylcarnitines, and supplementation of acylcarnitines is sufficient to recapitulate improved secondary cold responses. Overall, our data highlight the importance of heterogenous brown adipocyte populations for 'thermogenic memory', which may have therapeutic implications for leveraging short-term thermogenesis to counteract obesity.
Assuntos
Adipócitos Marrons , Tecido Adiposo Marrom , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Termogênese/fisiologiaRESUMO
Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-ß2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.
Assuntos
Sistema Nervoso Entérico , Doenças Inflamatórias Intestinais , Humanos , Glucocorticoides/farmacologia , Inflamação , Sistema Nervoso Entérico/fisiologia , Estresse PsicológicoRESUMO
The intestinal epithelium is a key physical interface that integrates dietary and microbial signals to regulate nutrient uptake and mucosal immune cell function. The transcriptional programs that regulate intestinal epithelial cell (IEC) quiescence, proliferation, and differentiation have been well characterized. However, how gene expression networks critical for IECs are posttranscriptionally regulated during homeostasis or inflammatory disease remains poorly understood. Herein, we show that a conserved family of microRNAs, miR-181, is significantly downregulated in IECs from patients with inflammatory bowel disease and mice with chemical-induced colitis. Strikingly, we showed that miR-181 expression within IECs, but not the hematopoietic system, is required for protection against severe colonic inflammation in response to epithelial injury in mice. Mechanistically, we showed that miR-181 expression increases the proliferative capacity of IECs, likely through the regulation of Wnt signaling, independently of the gut microbiota composition. As epithelial reconstitution is crucial to restore intestinal homeostasis after injury, the miR-181 family represents a potential therapeutic target against severe intestinal inflammation.
Assuntos
Colite , MicroRNAs , Animais , Colite/induzido quimicamente , Colite/genética , Células Epiteliais/metabolismo , Inflamação/genética , Inflamação/metabolismo , Mucosa Intestinal , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, resulting millions of infections and deaths with few effective interventions available. Here, we demonstrate that SARS-CoV-2 evades interferon (IFN) activation in respiratory epithelial cells, resulting in a delayed response in bystander cells. Since pretreatment with IFNs can block viral infection, we reasoned that pharmacological activation of innate immune pathways could control SARS-CoV-2 infection. To identify potent antiviral innate immune agonists, we screened a panel of 75 microbial ligands that activate diverse signaling pathways and identified cyclic dinucleotides (CDNs), canonical STING agonists, as antiviral. Since CDNs have poor bioavailability, we tested the small molecule STING agonist diABZI, and found that it potently inhibits SARS-CoV-2 infection of diverse strains including variants of concern (B.1.351) by transiently stimulating IFN signaling. Importantly, diABZI restricts viral replication in primary human bronchial epithelial cells and in mice in vivo. Our study provides evidence that activation of STING may represent a promising therapeutic strategy to control SARS-CoV-2.
Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , COVID-19/prevenção & controle , Interferons/imunologia , Proteínas de Membrana/agonistas , Animais , Linhagem Celular , Chlorocebus aethiops , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/virologia , Humanos , Evasão da Resposta Imune/imunologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/imunologia , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
The intestinal microbiota contains trillions of commensal microorganisms that shape multiple aspects of host physiology and disease. In contrast to the host's genome, the microbiome is amenable to change over the course of an organism's lifetime, providing an opportunity to therapeutically modulate the microbiome's impact on human pathophysiology. In this Perspective, we highlight environmental factors that regulate the temporal dynamics of the intestinal microbiome, with a particular focus on the different time scales at which they act. We propose that the identification of transient and intermediate states of microbiome responses to perturbations is essential for understanding the rules that govern the behavior of this ecosystem. The delineation of microbiome dynamics is also helpful for distinguishing cause and effect in microbiome responses to environmental stimuli. Understanding the dimension of time in host-microbiome interactions is therefore critical for therapeutic strategies that aim at short-term or long-term engineering of the intestinal microbial community.