Vagus nerve regulates the phagocytic and secretory activity of resident macrophages in the liver

Background & Aims The precise determination of non-alcoholic fatty liver disease (NAFLD) onset is challenging. Thus, the initial hepatic responses to fat accumulation, which may be fundamental to our understanding of NAFLD evolution and clinical outcomes, are largely unknown. Herein, we chronologically mapped the immunologic and metabolic changes in the liver during the early stages of fatty liver disease in mice and compared this with human NAFLD samples. Methods Liver biopsies from patients with NAFLD (NAFLD activity score [NAS] 2–3) were collected for gene expression profiling. Mice received a high-fat diet for short periods to mimic initial steatosis and the hepatic immune response was investigated using a combination of confocal intravital imaging, gene expression, cell isolation, flow cytometry and bone marrow transplantation assays. Results We observed major immunologic changes in patients with NAS 2–3 and in mice in the initial stages of NAFLD. In mice, these changes significantly increased mortality rates upon drug-induced liver injury, as well as predisposing mice to bacterial infections. Moreover, deletion of Toll-like receptor 4 in liver cells dampened tolerogenesis, particularly in Kupffer cells, in the initial stages of dietary insult. Conclusion The hepatic immune system acts as a sentinel for early and minor changes in hepatic lipid content, mounting a biphasic response upon dietary insult. Priming of liver immune cells by gut-derived Toll-like receptor 4 ligands plays an important role in liver tolerance in initial phases, but continuous exposure to insults may lead to damage and reduced ability to control infections. Lay summary Fatty liver is a very common form of hepatic disease, leading to millions of cases of cirrhosis every year. Patients are often asymptomatic until becoming very sick. Therefore, it is important that we expand our knowledge of the early stages of disease pathogenesis, to enable early diagnosis. Herein, we show that even in the early stages of fatty liver disease, there are significant alterations in genes involved in the inflammatory response, suggesting that the hepatic immune system is disturbed even following minor and undetectable changes in liver fat content. This could have implications for the diagnosis and clinical management of fatty liver disease.

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“…In a separate set of experiments, Kupffer cells were sorted as F4/80 + cells using magnetic beads. 22 …”

Section: Methodsmentioning

confidence: 99%

Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD

et al. 2020

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“…pY-STAT3 signals were slightly induced from CD11-positive macrophages in the liver of ConA-injected animals, suggesting the possible involvement of pY-STAT3 activity in macrophage activation that mediates proin ammatory reactions within the ganglia at the hepatic hilus and the portal space to postganglionic bers that are extended into hepatic vasculature, bile duct, and hepatic parenchyma (McCuskey, 2004;Sutherland, 1964;Skaaring & Bierring, 1976). It was also reported that the activation of α7 nicotinic acetylcholine receptors is involved in VNS-induced anti-in ammation in hepatic cells such as Kupffer cells and hepatic resident macrophages (Wang et al 2003;Hiramoto et al 2008;Nishio et al 2017;Fonseca et al 2019). However, the sequence of events connecting between ACh-releasing vagal efferent bers and AChR-expressing target cells in the liver remains unclear, and thus the characterization of mediators of intercellular cholinergic signaling, if any, should be of great importance to understand VNS-induced anti-in ammation in the liver.…”

Section: Discussionmentioning

confidence: 99%

Vagal Afferent Fibers Contribute to the Anti-Inflammatory Reactions by Vagus Nerve Stimulation in Concanavalin A Model of Hepatitis in Rats

Namgung

2020

Preprint

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Background: Increasing number of studies provide evidence that the vagus nerve stimulation (VNS) dampens inflammation in peripheral visceral organs. However, the effects of afferent fibers of the vagus nerve (AFVN) on anti-inflammation have not been clearly defined. Here, we investigate whether AFVN are involved in VNS-mediated regulation of hepatic production of proinflammatory cytokines. Methods: An animal model of hepatitis was generated by intraperitoneal injection of concanavalin A (ConA) into rats, and electrical stimulation was given to the hepatic branch of the vagus nerve. AFVN was selectively eliminated by treating animals with capsaicin (CAP). mRNA and protein expression in target tissues was analyzed by RT-PCR, real-time PCR, western blotting and immunofluorescence staining.Results: TNF-α, IL-1β, and IL-6 mRNAs and proteins that were induced by ConA in the liver macrophages were significantly reduced by the electrical stimulation of the hepatic branch of the vagus nerve (hVNS). hVNS also induced an increase in phospho-STAT3 in the liver macrophages of ConA-injected animals, suggesting the activation of STAT3 transcription factor associated with cholinergic anti-inflammation. Capsaicin (CAP) treatment deteriorated transient receptor potential vanilloid 1 (TRPV1)-positive neurons and also induced an increase in apoptotic caspase-3 signals in nodose ganglion (NG) neurons. Concomitantly, CAP suppressed choline acetyltransferase (ChAT) expression that was induced by hVNS in DMV neurons of ConA-injected animals. Furthermore, hVNS-mediated downregulation of TNF-α, IL-1β, and IL-6 expression was reduced by CAP administration. Conclusions: Our data indicate that the activity of AFVN contributes to hepatic anti-inflammatory responses mediated by hVNS in ConA model of hepatitis in rats.

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“…The activation of macrophages has been reported to be regulated by ACh [ 40 ]. Vagotomy, knockdown of the vesicular ACh transporter, and administration of an ACh-antagonist promoted the phagocytosis of macrophages (Kupffer cells) in the mouse liver [ 10 ]. In addition, inflammatory activity is inhibited by ACh through the nicotinic ACh receptor of peritoneal macrophages from mice [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional analysis of neural connectivity with cells in rat ileal mucosa by serial block-face scanning electron microscopy

Nakanishi

Mantani

Haruta

et al. 2020

The Journal of Veterinary Medical Science

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The comprehensive targets of innervation in the intestinal mucosa are unknown, partly because of the diversity of cell types and the complexity of the neural circuits. Herein, we investigated the comprehensive targets of neural connectivity and analyzed the precise characteristics of their contact structures in the mucosa of rat ileum. We examined target cells of neural connections and the characteristics of their contact structures by serial block-face scanning electron microscopy at four portions of the rat ileal mucosa: the apical and basal portions in the villi, and the lateral and basal portions around/in the crypts. Nerve fibers were in contact with several types of fibroblast-like cells (FBLCs), macrophage-like cells, eosinophils, lymphocyte-like cells, and other types of cells. The nerve fibers almost always ran more inside of lamina propria than subepithelial FBLC, and thus contacts with epithelial cells were very scarce. The contact structures of the nerve fibers were usually contained synaptic vesicle-like structures, and we classified them into patterns based on the number of nerve fiber contacting the target cells at one site, the maximum diameter of the contact structures, and the relationship between nerve fibers and nerve bundles. The contact structures for each type of cells occasionally dug into the cellular bodies of the target cells. We revealed the comprehensive targets of neural connectivity based on the characteristics of contact structures, and identified FBLCs, immunocompetent cells, and eosinophils as the candidate targets for innervation in the rat ileal mucosa.

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Vagus nerve regulates the phagocytic and secretory activity of resident macrophages in the liver

Cited by 33 publications

References 47 publications

Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD

Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD

Vagal Afferent Fibers Contribute to the Anti-Inflammatory Reactions by Vagus Nerve Stimulation in Concanavalin A Model of Hepatitis in Rats

Three-dimensional analysis of neural connectivity with cells in rat ileal mucosa by serial block-face scanning electron microscopy

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