With the continuous advancement of science, our understanding of the human body is getting deeper and deeper. A recent review published in the journal Advanced Science directs our eyes to the unexpected interweaving between the nervous system and the immune system. This review presents new insights into the interactions between metabolic organs and the immune system, opening up entirely new avenues for future diseases**.
A Magical Encounter: Background**.
The metabolic stability of the body is inseparable from the silent regulation of the sympathetic nervous system. Advances in neurology and functional assessment have led to a deeper understanding of the metabolic processes regulated by neural networks, providing more accurate tools for neurological research. The sympathetic nervous system not only regulates metabolism, but also works with the immune system to prepare the body for a variety of internal and external challenges. The review highlights the complexity of liver, gut, pancreas, and adipose tissue metabolism, revealing novel pathways between nerves and immunity.
Pancreas: where nerves and immunity meet.
The pancreas plays an important role in the body's internal and external secretions. Although we already know about the role of the nervous system in regulating the pancreas, there is growing evidence that the immune system also plays a role here. The pancreas is innervated by the sympathetic nerves, which receive signals from the spinal cord. The sympathetic nerves control blood vessels, pancreatic islets, and acinar secretory cells through the mediation of norepinephrine. This control affects blood sugar levels, increasing blood sugar while decreasing insulin secretion and blood flow. In addition, signals from sensory nerves help maintain overall function, ensuring the proper functioning of the pancreas and glucose metabolism.
Neuromodulation of pancreatic islets is essential for the prevention of autoimmune diabetes. In type 1 diabetes (T1D), the loss of sympathetic nerves affects the autoimmune response. Inhibition of sympathetic nerves or blockade of 1 adrenergic receptors is effective in preventing autoimmune responses. Macrophages in pancreatic islets often exhibit a pro-inflammatory state, leading to inflammation and sympathetic damage. Targeting adrenergic receptors on immune cells reduces the production of pro-inflammatory cytokines, protects cell function, and slows the development of type 1 diabetes in mice.
The liver: the mystery of neuroimmunity.
As a center that regulates blood flow, glucose and lipid homeostasis, and immune processes, the liver receives sympathetic innervation from the ganglia. Neural activity in the liver has an effect on glucose metabolism, promoting glycogen breakdown, hepatic gluconeogenesis and inhibiting glycogen production. This regulation includes adrenergic receptors and neuropeptides. Liver transplant studies have shown that the autonomic nervous system plays an important role in the long-term regulation of liver metabolism. In nonalcoholic fatty liver disease (NAFLD), increased sympathetic activity and decreased parasympathetic tone contribute to disease progression.
Immune cells in the liver are closely related to sympathetic neurons. In hepatocellular carcinoma (HCC), activation of 1 adrenergic receptors on Kupffer cells promotes the development of HCC and maintains an inflammatory state. The sympathetic nerves affect the number of NKT cells, and norepinephrine** restores NKT cell levels in the liver and regulates cytokine production. Studies have also shown that sympathetic innervation plays a role in protecting the liver from acute hepatitis and promoting liver regeneration through the ILC1-IL-22 axis. Further research on the bidirectional relationship between nerve and liver immune cells needs to be further studied to better understand these underlying mechanisms.
Gut: The miraculous source of life.
The gastrointestinal tract is the body's largest immune reservoir and is made up of a variety of cells that are regulated by complex innervations. The axons of sympathetic neurons extend into the intestinal wall, where specific receptors are found in intestinal stem cells and a variety of intestinal epithelial cells, thereby regulating digestive functions, including secretion, motility, perception, and epithelial cell proliferation. Studies have shown that SNS is associated with a variety of diseases, such as intestinal parasitic infections, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS).
Neuroimmune interactions in the gastrointestinal tract affect immune cells such as macrophages, lymphocytes, mast cells, dendritic cells, and innate lymphocytes (ILCs). Sympathetic innervation helps different regions of the gastrointestinal tract to form different macrophage phenotypes, influencing tissue protective response and infection outcomes. Neuron-ILC2 units in the gut highlight the importance of adrenergic neurons in regulating ILC2 activity, which is essential for the immune response against helminth infection. In addition, bacteria possessing functional adrenergic receptors respond to host catecholamines, suggesting a potential strategy to fight intestinal bacterial infections.
Adipose tissue: the discovery of more functions.
Accumulating evidence suggests that adipose tissue is not only a passive fat reservoir, but also an active endocrine organ, with important implications for glucose homeostasis, thermogenesis, insulin resistance, and immune response. Sympathetic innervation is present in white and brown adipose tissue. Macrophages, eosinophils, ILC2, and other immune cells in adipose tissue respond to sympathetic signals, influencing functions such as thermogenesis and inflammation. Disruption of neuroimmune interactions may impair nerve integrity and tissue function, highlighting the importance of maintaining neuroimmune homeostasis for optimal metabolic health.
The Road Ahead: Conclusions and Prospects.
This review highlights the critical role of the sympathetic nervous system in coordinating the metabolism of various organs, with particular emphasis on its impact on the immune microenvironment. There is a growing recognition that novel strategies targeting the sympathetic nervous system have potential efficacy in diseases such as metabolic disorders, chronic pain, cardiovascular problems, and cancer. This amazing neuroimmune alliance opens the door for us to delve deeper into the mysteries of the body, and also gives us a lot of anticipation for the future of disease**.
Reference: The sympathetic-immune milieu in metabolic health and diseases: insights from pancreas, liver, intestine, and adipose tissues ren, w., hua, m., cao, f., zeng, w., advanced science, 2306128 (2023), doi: