Neuroimmune modulation in liver pathophysiology

Abstract

The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.

Keywords: Autonomic nervous system; Liver disease; Neuroimmune system; Parasympathetic nervous system; Sympathetic nervous system.

Fig. 1

The classification of the nervous system and the summary of peripheral nervous system (PNS). A Classification of the nervous system. B Summary of efferent pathways in the PNS. The autonomic nervous system is organized in three anatomical and biochemical distinct systems, the sympathetic nervous system (SNS, in red), the parasympathetic nervous system (PNS, in blue) and the enteric nervous system (ENS, Fig. 1D), respectively. C Summary of the afferent pathways in the PNS (in the liver and gut). D Schematic diagram of the ENS. The ENS is located within intestinal tissues and has a characteristic architecture. CNS central nervous system, ENS enteric nervous system, PNS peripheral nervous system, PSNS parasympathetic nerve system, SNS sympathetic nerve system, III the third cranial nerve, VII the seventh cranial nerve, IX the ninth cranial nerve, X the tenth cranial nerve

Fig. 2

Hepatic neuroanatomy. A Origin and concomitant of hepatic plexus. The anterior plexus, originating from the left portion of the celiac plexus and the right abdominal branch of the vagus, forms a network of nerves surrounding the hepatic artery. Meanwhile, the posterior plexus, derived from the right portion of the celiac plexus, is located around the portal vein with occasional innervations accompanying the hepatic vein. B Anatomy of the intrinsic sympathetic and parasympathetic nerve fibers. In all mammalian species, sympathetic and parasympathetic fibers surround the portal are an humans and guinea pigs but not rats. sympathetic fibers course into liver sinusoids. C Innervation of the human liver. Within the liver, nerves are found around the hepatic artery, portal vein, and bile ducts. Sympathetic nerves, but not parasympathetic nerves, synapse on hepatocytes as well. LSEC liver sinusoids endothelial cell

Fig. 3

Hepatic immune system and functions. A Functions of the liver. The mammalian liver is a complex organ consisting of diverse cell types that perform multiple physiological functions including digestion, detoxication, metabolism, biotransformation, and immune. B Hepatic immune system. The liver’s immune defense mechanism primarily depends on a complex network of immune cells and non-immune cells, the latter of which play immune roles by recruiting proinflammatory immune cells and simultaneously producing inflammatory cytokines

Fig. 4

Neuronal regulation of immune activation. A Outline. An overview of inter-regulation of the nervous system and the immune system. B Endocrine pathways. The endocrine signals enable the synchronization of complex physiological processes and immune activity. C Neuronal efferent pathways. Noradrenaline (recognized by α-adrenergic and β-adrenergic receptors) is the primary neurotransmitter of the SNS, while acetylcholine (ACh; recognized by nicotinic and muscarinic ACh receptors) is the primary PSNS neurotransmitter. Both of which can affect activity of immune organs and immune cells. D Meningeal lymphatic vessels. The meningeal lymphatic system can impact both the central and peripheral immune response by transporting immune cells and antigens from the brain to the peripheral immune system. ACTH adrenocorticotropic hormone, ANS autonomic nervous system, Ach acetylcholine, AI Alzheimer’s disease, AVP arginine vasopressin, CNS central nervous system, CCL21 C–C motif chemokine ligand 21, Epi epinephrine, FSH follicle-stimulating hormone, GH growth hormone, LH luteinizing hormone, M-R muscarinic cholinergic receptor, MS multiple sclerosis, N1-R nicotinic cholinergic receptor type 1, NA norepinephrine, OXT oxytocin, PVN paraventricular nucleus, PRL prolactin, PNS peripheral nervous system, PSNS parasympathetic nerve system, PROX1 prospero homeobox 1, SON supraoptic nucleus, TSH thyroid stimulating hormone, VEGFR3 also known as “FLT4,” fms related receptor tyrosine kinase 4, α/ꞵ-R adrenergic cholinergic receptor

Fig. 5

Immune regulation of neuronal function. The pathways in which immune influences on the nervous system consist of cytokines, afferent neural inputs, and chemoreceptors (including osmoreceptors, ion receptors, and metabolic substance receptors). DAPMs damage-associated molecule patterns, GLUT2 glucose transporter 2, NKCC1 Na ⁺-K⁺-2Cl⁻ cotransporter, PKC protein kinase C, PAMPs pathogen-associated molecular patterns, TRPV4 transient receptor potential vanilloid 4

Fig. 6

The neuroimmune crosstalk in liver pathology. The sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS) play a crucial role in the development and progression of liver diseases, including liver injury (A), liver fibrosis (B), MAFLD (C), and HCC (D). The two 3D imagines of immunolabeling in the “NAFLD” part are from ref 158. HSCs hepatic stellate cells, HCC hepatocellular carcinoma, IL-6 interleukin 6, MAOA monoamine oxidase A, MAFLD metabolic dysfunction-associated fatty liver disease, NAFLD non-alcoholic fatty liver disease, PSNS parasympathetic nervous system, SNS sympathetic nervous system, TNF-α tumor necrosis factor α, 6-OHDA 6-hydroxydopamine, α7nAChR α7 nicotinic acetylcholine receptor, α/ꞵ-R adrenergic cholinergic receptor

Fig. 7

Liver pathology affecting the CNS. The possible mechanisms of how liver pathology affects brain cognitive function in diseases of hepatic encephalopathy (A), chronic liver disease (CLD)-associated fatigue (B), depression, and anxiety (C). CLD chronic liver disease, CNS central nervous system, HE hepatic encephalopathy, HCV hepatitis c virus, IFN interferon, NO nitric oxide, PBC primary biliary cirrhosis, TLR2 toll-like receptor 2

Fig. 8

The Clinical translations and future directions of the neuroimmune crosstalk in the liver. DBS deep brain stimulation, IBD inflammatory bowel disease, TMS transcranial magnetic stimulation, tDCS transcranial direct current stimulation, TUS transcranial ultrasound stimulation, VNS vagus nerve stimulation, α7nAChR α7 nicotinic acetylcholine receptor