RESUMO
Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor+ (LepR+) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease.
Assuntos
Acetilcolina , Hematopoese , Animais , Linfócitos B , Colinérgicos , Hematopoese/genética , Camundongos , Nicho de Células-TroncoRESUMO
Interactions between the immune and central nervous systems strongly influence brain health. Although the blood-brain barrier restricts this crosstalk, we now know that meningeal gateways through brain border tissues facilitate intersystem communication. Cerebrospinal fluid (CSF), which interfaces with the glymphatic system and thereby drains the brain's interstitial and perivascular spaces, facilitates outward signaling beyond the blood-brain barrier. In the present study, we report that CSF can exit into the skull bone marrow. Fluorescent tracers injected into the cisterna magna of mice migrate along perivascular spaces of dural blood vessels and then travel through hundreds of sub-millimeter skull channels into the calvarial marrow. During meningitis, bacteria hijack this route to invade the skull's hematopoietic niches and initiate cranial hematopoiesis ahead of remote tibial sites. As skull channels also directly provide leukocytes to meninges, the privileged sampling of brain-derived danger signals in CSF by regional marrow may have broad implications for inflammatory neurological disorders.
Assuntos
Sistema Glinfático , Meningites Bacterianas , Animais , Medula Óssea , Encéfalo/irrigação sanguínea , Líquido Cefalorraquidiano , Sistema Glinfático/fisiologia , Hematopoese , Camundongos , CrânioRESUMO
Thyroid-stimulating hormone (TSH) treatment activates inhibitor of NF-κB/nuclear factor κB (IκB/NFκB) and extracellular signal-regulated kinase (ERK)-P38 in macrophages, but how these pathways are activated, and how they contribute to the proinflammatory effect of TSH on macrophages remain unknown. The TSH receptor (TSHR) is coupled to 4 subfamilies of G proteins (Gs, Gi/o, Gq/11, and G12/13) for its downstream signaling. This study investigated the G protein subtypes responsible for the proinflammatory effect of TSH on macrophages. qPCR showed that Gi2, Gi3, Gas, Gq, G11, G12, G13, and G15 are abundantly expressed by macrophages. The contribution of different G protein pathways to the proinflammatory effect was studied by the corresponding inhibitors or siRNA interference. While TSH-induced IκB phosphorylation was not inhibited by Gs inhibitor NF449, Gi inhibitor pertussis toxin, or Gq or G11 siRNA, it was blocked by phospholipase C inhibitor U73122 or G15 siRNA interference. TSH-induced ERK and P38 phosphorylation was blocked by G13 but not G12 siRNA interference. Interference of either G13 or G15 could block the proinflammatory effect of TSH on macrophages. The present study demonstrate that TSH activates macrophage inflammation by the G13/ERK-P38/Rho GTPase and G15/phospholipase C (PLC)/protein kinases C (PKCs)/IκB pathways.
Assuntos
Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Macrófagos/metabolismo , Tireotropina/metabolismo , Animais , Proteínas I-kappa B/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Células RAW 264.7 , Receptores Acoplados a Proteínas G/metabolismo , Fosfolipases Tipo C/metabolismoRESUMO
Subclinical hypothyroidism is associated with cardiovascular diseases, yet the underlying mechanism remains largely unknown. Herein, in a common population (n = 1,103), TSH level was found to be independently correlated with both carotid plaque prevalence and intima-media thickness. Consistently, TSH receptor ablation in ApoE -/- mice attenuated atherogenesis, accompanied by decreased vascular inflammation and macrophage burden in atherosclerotic plaques. These results were also observed in myeloid-specific Tshr-deficient ApoE -/- mice, which indicated macrophages to be a critical target of the proinflammatory and atherogenic effects of TSH. In vitro experiments further revealed that TSH activated MAPKs (ERK1/2, p38α, and JNK) and IκB/p65 pathways in macrophages and increased inflammatory cytokine production and their recruitment of monocytes. Thus, the present study has elucidated the new mechanisms by which TSH, as an independent risk factor of atherosclerosis, aggravates vascular inflammation and contributes to atherogenesis.
Assuntos
Aterosclerose/epidemiologia , Aterosclerose/metabolismo , Espessura Intima-Media Carotídea , Macrófagos/metabolismo , Placa Aterosclerótica/epidemiologia , Placa Aterosclerótica/metabolismo , Tireotropina/metabolismo , Idoso , Animais , Citocinas/metabolismo , Feminino , Seguimentos , Humanos , Proteínas I-kappa B/metabolismo , Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Prevalência , Células RAW 264.7 , Interferência de RNA , Receptores da Tireotropina/genéticaRESUMO
Nonalcoholic fatty liver disease (NAFLD) currently represents the most common hepatic disease worldwide and is closely linked to cardiovascular disease, obesity and diabetes mellitus. This study aimed to investigate NAFLD and its influence on different monocyte subpopulations to determine the presence of significant associations. A total of 3 monocyte subpopulations were investigated, i.e. classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++). Of the participants 261 were included in this study (nâ¯= 53 with NAFLD, nâ¯= 208 controls). Ultrasonography was used to diagnose NAFLD and exclude other morphologic causes of liver diseases and other tests (including medical history inquiries and detection of hepatitis virus) were performed to exclude other causes of parenchymal liver disease. Classical inflammatory and metabolic-related NAFLD biomarkers were also determined. In contrast to the healthy control group, the intermediate monocyte fraction was increased in NAFLD patients (pâ¯= 0.032), while the classical monocyte fraction was decreased (pâ¯= 0.025). Intermediate monocyte fraction, body mass index (BMI) and tumor necrosis factor alpha (TNF-α) were independent risk factors for NAFLD. Classical, non-classical and intermediate monocytes fraction were strongly associated with age, triglyceride, and waist circumference. This study suggests that the intermediate monocyte fraction in peripheral blood is likely related to the aggravation of NAFLD.
Assuntos
Monócitos/classificação , Hepatopatia Gordurosa não Alcoólica , Índice de Massa Corporal , Estudos de Casos e Controles , Humanos , Monócitos/citologia , Monócitos/patologia , Hepatopatia Gordurosa não Alcoólica/sangueRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a chronic and progressive liver disease with an increased risk of morbidity and mortality. However, so far no specific pharmacotherapy has been approved. Gynostemma pentaphylla (Thunb.) Makino (GP) is a traditional Chinese medicine that is widely used against hyperlipemia as well as hyperglycemia. This study aims to evaluate the effect of GP on NAFLD and explore the possible mechanism. METHODS: High-fat-diet induced NAFLD mice model were orally administrated with GP at dose of 11.7 g/kg or equivalent volume of distilled water once a day for 16 weeks. Body weight, food intake and energy expenditure were assessed to evaluate the general condition of mice. The triglycerides, total cholesterol content in the liver and liver histopathology, serum lipid profile and serum insulin level, fecal microbiome, hepatic microRNAs and relative target genes were analyzed. RESULTS: Mice in GP treatment group displayed improved hepatic triglycerides content with lower lipid droplet in hepatocyte and NAFLD activity score. Besides, GP treatment altered the composition of gut microbiota and the relative abundance of some of the key components that are implicated in metabolic disorders, especially phylum Firmicutes (Eubacterium, Blautia, Clostridium and Lactobacillus). Several hepatic microRNAs were downregulated by GP treatment such as miR-130a, miR-34a, miR-29a, miR-199a, among which the expression miR-34a was altered by more than four-fold compared to that of HFD group (3:14). The correlation analysis showed that miR-34a was strongly related to the change of gut microbiota especially phylum Firmicutes (R = 0.796). Additionally, the target genes of miR-34a (HNF4α, PPARα and PPARα) were restored by GP both in mRNA and protein levels. CONCLUSION: Our results suggested that GP modulated the gut microbiota and suppressed hepatic miR-34a, which was associated with the amelioration of hepatic steatosis.
RESUMO
Metabolic disorders are classified clinically as a complex and varied group of diseases including metabolic syndrome, obesity, and diabetes mellitus. Fat toxicity, chronic inflammation, and oxidative stress, which may change cellular functions, are considered to play an essential role in the pathogenetic progress of metabolic disorders. Recent studies have found that cells secrete nanoscale vesicles containing proteins, lipids, nucleic acids, and membrane receptors, which mediate signal transduction and material transport to neighboring and distant cells. Exosomes, one type of such vesicles, are reported to participate in multiple pathological processes including tumor metastasis, atherosclerosis, chronic inflammation, and insulin resistance. Research on exosomes has focused mainly on the proteins they contain, but recently the function of exosome-associated microRNA has drawn a lot of attention. Exosome-associated microRNAs regulate the physiological function and pathological processes of metabolic disorders. They may also be useful as novel diagnostics and therapeutics given their special features of non-immunogenicity and quick extraction. In this paper, we summarize the structure, content, and functions of exosomes and the potential diagnostic and therapeutic applications of exosome-associated microRNAs in the treatment of metabolic disorders.
Assuntos
Exossomos/fisiologia , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/terapia , MicroRNAs/fisiologia , Tecido Adiposo/metabolismo , Animais , Humanos , Doenças Metabólicas/genética , Microambiente TumoralRESUMO
The association between subclinical hypothyroidism (SH) and cardiovascular disease has received increasing attention in recent years. The predisposition of patients with SH to endothelial dysfunction, an early sign of atherosclerosis, has been observed. This predisposition may be partially explained by the factors also found in patients with SH, including changes in lipid profile, low grade chronic inflammation, oxidative stress and insulin resistance. The proportional risks of endothelial dysfunction to thyroid stimulating hormone (TSH) also indicate that the action of TSH on extra thyroidal-stimulating hormone receptor (TSHR) is a possible mechanism underlying the correlation, which has later been supported by the associated basic studies. L-thyroxine replacement therapy appears to improve the aforementioned aspects, whereas there remain certain controversies, particularly for the elderly. Thus, more study data are required to confirm the benefit of L-thyroxine treatment for patients with SH.