Neuro-immune-metabolism: The tripod system of homeostasis

Abstract

Homeostatic regulation of cellular and molecular processes is essential for the efficient physiological functioning of body organs. It requires an intricate balance of several networks throughout the body, most notable being the nervous, immune and metabolic systems. Several studies have reported the interactions between neuro-immune, immune-metabolic and neuro-metabolic pathways. Current review aims to integrate the information and show that neuro, immune and metabolic systems form the triumvirate of homeostasis. It focuses on the cellular and molecular interactions occurring in the extremities and intestine, which are innervated by the peripheral nervous system and for the intestine in particular the enteric nervous system. While the interdependence of neuro-immune-metabolic pathways provides a fallback mechanism in case of disruption of homeostasis, in chronic pathologies of continued disequilibrium, the collapse of one system spreads to the other interacting networks as well. Current review illustrates this domino-effect using diabetes as the main example. Together, this review attempts to provide a holistic picture of the integrated network of neuro-immune-metabolism and attempts to broaden the outlook when devising a scientific study or a treatment strategy.

Keywords: Diabetes; Homeostasis; Immune-metabolic interactions; Neuro-immune interactions; Neuro-metabolic interactions; Obesity; Peripheral nervous system.

Fig. 1. Neuro-immune-metabolic interactions during homeostasis.

The upper panel shows interactions in the intestine. Glucose is used as a metabolic substrate by all neurons and immune cells Th2 cells, Th17 cells, B cells and ILC3. The M2 macrophages, ILC2, naïve T cells and also B cells utilize fatty oxidation pathway to derive energy. The naïve T cells derive energy from amino acid metabolism as well. The immune cells secrete factors, which affect the enteric neuronal functions. For e.g., IL-10 and IL-4 bind to their cognate receptors on neurons to prevent inflammatory signaling. Neuronal function is also affected availability of metabolic substrates. They in turn regulate the glycolysis via the neuropeptides POMC, GLP-1 and Gal, whereas norepinephrine is required for efficient lipolysis via fatty acid oxidation. Together these interactions are required for physiological functions in the gut namely gut motility, mucosal barrier integrity and nutrient absorption. The lower panel depicts interactions occurring in the extremities. The legs, for e.g., are innervated by the sensory neurons broadly classified as CGRP⁺, NF200⁺ or IB4 binding. A sensory stimulus triggers cellular interactions aimed to restore homeostasis. The neurons release the neuropeptides CGRP and SP, which recruit macrophages, mast cells, neutrophils and DCs. The inflammatory factors such as TNF-α, histamines may cause proinflammatory signaling and hyperexcitability of neurons. However, antiinflammatory cytokines released by the immune cells (IL-10) and inhibitory neuropeptides released by the neurons (POMC and GABA) deactivate the immune cells and also prevent neuronal hyperexcitability and ensuing pain. The immune cells and neurons utilize glycolysis to perform these functions.

Fig. 2. Dysfunction neuro-immune-metabolic interactions during diabetes.

Upper panel shows dysfunction in the intestine. Hyperglycaemia, dyslipidemia and oxidative stress together causes increased proliferation and activation of M1 macrophages, B cells, Th1 cells, CD8⁺ T cells, DC and mast cell degranulation. The proinflammatory mediators released by these immune cells (IL-1ß, IL-6, TNF-α, IFN-γ) cause chronic neuronal excitation. Elevated glucose and fatty acid levels are also responsible for neuronal excitation. This leads to reduced levels of norepinephrine and increased levels of SP and CGRP. Dysbalance in neurotransmitters is unable to regulate metabolic pathways, further contributing metabolic distress. For instance, inefficient fatty acid oxidation and increased lipid storage can be attributed to decreased norepinephrine levels. Together this results in heightened inflammation, compromised mucosal barrier integrity, uncontrolled glucose levels and leads to abdominal pain and altered gut motility. Lower panel shows dysfunction in the extremities. Hyperglycaemia causes neuronal activation and chronic release of excitatory neurotransmitters (CGRP and SP). These recruit the immune cells, which also have a proinflammatory phenotype due the dysregulated metabolite levels. The immune cells contribute to inflammation and neuronal hyperexcitability by releasing proinflammatory mediators (IL-1ß, Il-6, TNF-α, IFN-γ). The decreased levels of inhibitory neuropeptides (POMC) is unable to terminate the excitatory transmission leading to excitotoxicity, hypersensitivity and eventual neuronal degeneration.