Related Experiment Video
Updated: Jun 3, 2025
Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss
Published on: July 19, 2024
Modulating intestinal neuroimmune VIPergic signaling attenuates the reduction in ILC3-derived IL-22 and hepatic
Henry H Nguyen1,2, Jhimmy Talbot1,3, Dayi Li1
1Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
Background:
Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD) is a major driver of cirrhosis and liver-related mortality. However, therapeutic options for MASLD, including prevention of liver steatosis, are limited. We previously described that vasoactive intestinal peptide-producing neurons (VIP-neurons) regulate the efficiency of intestinal dietary fat absorption and IL-22 production by type 3 innate lymphoid cells (ILC3) in the intestine. Given the described hepatoprotective role of IL-22, we hypothesize that modulation of this neuroimmune circuit could potentially be an innovative approach for the control of liver steatosis.
Methods:
We used a model of diet-induced MASLD by exposing mice to a high-fat diet (HFD) for 16 weeks, when the development of liver steatosis was first observed in our animals. We characterized IL-22 production by intestinal ILC3 at this dietary endpoint. We then evaluated whether communication between VIP-neurons and ILC3 affected IL-22 production and MASLD development by exposing mice with a conditional genetic deletion of Vipr2 in ILC3 (Rorc(t)CreVipr2fl/fl) to the HFD. We also performed intermittent global inhibition of VIP-neurons using a chemogenetic inhibitory approach (VipIres-CrehM4DiLSL) in HFD-fed mice.
Results:
Production of IL-22 by intestinal ILC3 is reduced in steatotic mice that were exposed to an HFD for 16 weeks. Targeted deletion of VIP receptor 2 in ILC3 resulted in higher production of IL-22 in ILC3 and was associated with a significant reduction in liver steatosis in mice under HFD. Global inhibition of VIP-producing neurons also resulted in a significant reduction in liver steatosis.
Conclusions:
Modulating VIPergic neuroimmune signaling can ameliorate the development of hepatic steatosis induced by a surplus of fat ingestion in the diet. This neuroimmune pathway should be further investigated as a potential therapeutic avenue in MASLD.
Insights
Targeting VIPergic neuroimmune signaling shows promise for treating metabolic dysfunction-associated steatotic liver disease (MASLD). Inhibiting VIP-producing neurons or their receptors reduced liver steatosis in mice, suggesting a new therapeutic approach for MASLD.
Area of Science:
- Neuroimmunology
- Hepatology
- Gastroenterology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of liver cirrhosis and mortality, with limited therapeutic options.
- Vasoactive intestinal peptide-producing neurons (VIP-neurons) influence intestinal fat absorption and IL-22 production by innate lymphoid cells (ILC3).
- IL-22 has a known hepatoprotective role, suggesting the VIP-neuron-ILC3 axis as a potential therapeutic target for MASLD.
Purpose of the Study:
- To investigate the role of the VIP-neuron-ILC3 neuroimmune axis in the development of diet-induced MASLD.
- To determine if modulating this pathway can ameliorate liver steatosis.
Main Methods:
- Mice were fed a high-fat diet (HFD) for 16 weeks to induce MASLD.
- IL-22 production by intestinal ILC3 was characterized in steatotic mice.
- Genetic deletion of VIP receptor 2 in ILC3 and chemogenetic inhibition of VIP-neurons were employed in HFD-fed mice.
Main Results:
- IL-22 production by intestinal ILC3 was reduced in mice with HFD-induced MASLD.
- Targeting VIP receptor 2 in ILC3 increased IL-22 production and significantly reduced liver steatosis.
- Global inhibition of VIP-neurons also led to a significant reduction in liver steatosis.
Conclusions:
- Modulating VIPergic neuroimmune signaling can effectively reduce diet-induced hepatic steatosis.
- This neuroimmune pathway represents a promising novel therapeutic target for MASLD.
- Further investigation into this pathway is warranted for MASLD treatment development.
More Related Videos
09:04DNBS/TNBS Colitis Models: Providing Insights Into Inflammatory Bowel Disease and Effects of Dietary Fat
Published on: February 27, 2014
06:43Increased Recovery Time and Decreased LPS Administration to Study the Vagus Nerve Stimulation Mechanisms in Limited Inflammatory Responses
Published on: March 29, 2017
