Nguyen Henry H, Talbot Jhimmy, Li Dayi, Raghavan Varsha, Littman Dan R
Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
Department of Medicine and Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Hepatol Commun. 2024 Oct 17;8(11). doi: 10.1097/HC9.0000000000000528. eCollection 2024 Nov 1.
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.
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.
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.
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.
代谢功能障碍相关脂肪性肝病（MASLD，以前称为非酒精性脂肪性肝病）是肝硬化和肝脏相关死亡率的主要驱动因素。然而，MASLD的治疗选择，包括预防肝脏脂肪变性，是有限的。我们之前描述过，产生血管活性肠肽的神经元（VIP神经元）调节肠道膳食脂肪吸收效率以及肠道中3型天然淋巴细胞（ILC3）产生白细胞介素-22（IL-22）的过程。鉴于已描述的IL-22的肝脏保护作用，我们假设调节这种神经免疫回路可能是控制肝脏脂肪变性的一种创新方法。
我们通过让小鼠食用高脂肪饮食（HFD）16周来建立饮食诱导的MASLD模型，此时我们首次在动物中观察到肝脏脂肪变性的发展。我们在这个饮食终点对肠道ILC3产生IL-22的情况进行了表征。然后，我们通过让ILC3中条件性基因缺失Vipr2的小鼠（Rorc(t)CreVipr2fl/fl）食用HFD，评估VIP神经元与ILC3之间的通讯是否影响IL-22的产生和MASLD的发展。我们还在喂食HFD的小鼠中使用化学遗传抑制方法（VipIres-CrehM4DiLSL）对VIP神经元进行间歇性全局抑制。
在食用HFD 16周的脂肪变性小鼠中，肠道ILC3产生IL-22的量减少。ILC3中VIP受体2的靶向缺失导致ILC3中IL-22的产生增加，并与HFD喂养小鼠肝脏脂肪变性的显著减轻相关。对产生VIP的神经元进行全局抑制也导致肝脏脂肪变性显著减轻。
调节VIP能神经免疫信号传导可改善饮食中脂肪摄入过多诱导的肝脂肪变性的发展。这条神经免疫途径应作为MASLD潜在的治疗途径进一步研究。
