The role of cellular and molecular neuroimmune crosstalk in gut immunity

Abstract

The gastrointestinal tract is densely innervated by the peripheral nervous system and populated by the immune system. These two systems critically coordinate the sensations of and adaptations to dietary, microbial, and damaging stimuli from the external and internal microenvironment during tissue homeostasis and inflammation. The brain receives and integrates ascending sensory signals from the gut and transduces descending signals back to the gut via autonomic neurons. Neurons regulate intestinal immune responses through the action of local axon reflexes or through neuronal circuits via the gut-brain axis. This neuroimmune crosstalk is critical for gut homeostatic maintenance and disease resolution. In this review, we discuss the roles of distinct types of gut-innervating neurons in the modulation of intestinal mucosal immunity. We will focus on the molecular mechanisms governing how different immune cells respond to neural signals in host defense and inflammation. We also discuss the therapeutic potential of strategies targeting neuroimmune crosstalk for intestinal diseases.

Keywords: Gut; Host defense; Neuroimmune; Neuroimmunology; Sensory.

Fig. 1

Neuroanatomy of the gastrointestinal tract. The gastrointestinal tract is innervated by gut-extrinsic and gut-intrinsic sensory and autonomic neurons. Extrinsic parasympathetic, sympathetic and sensory neurons originate in the brainstem and spinal cord, projecting to the outer muscle layers and the inner mucosa of the gut. Sensory neurons are pseudounipolar neurons that have their cell bodies in the dorsal root ganglia (DRG) and nodose/jugular vagal ganglia (VG), and they transduce signals from the gut to the spinal cord and brainstem, respectively. Sympathetic neurons consist of preganglionic neurons in the spinal cord that project to the sympathetic ganglia, where they synapse with postganglionic neurons that project to the gut. Parasympathetic neurons communicate from the brainstem to the gut via the vagus nerve. Gut-intrinsic enteric neurons reside in the myenteric and submucosal plexus layers of the intestine and innervate all intestinal layers

Fig. 2

Sensory neuron regulation of gut immunity. In response to microbial and dietary cues, TRPV1⁺Nav1.8⁺ DRG nociceptor neurons are activated, leading to release of the neuropeptides CGRP and Substance P (SP). CGRP suppresses the differentiation of microfold (M) cells in the Peyer’s patch dome, thereby limiting S. Typhimurium pathogen invasion. CGRP also promotes goblet cell mucus production through its co-receptor Ramp1, which mediates gut barrier protection against colitis. SP maintains gut microbiota homeostasis, which contributes to mucosal protection. SP also promotes mast cell degranulation, which contributes to visceral pain and inflammation

Fig. 3

Enteric neuron regulation of gut immunity. Enteric neurons are heterogeneous and can release cytokines (e.g., IL-18 and IL-6) and neuropeptides (e.g., neuromedin U (NMU), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP)) to regulate immune function. A Neuronal IL-18 regulates goblet cell expression of antimicrobial peptides, which mediates host protection against intestinal S. Typhimurium infection. B Neuronal IL-6 inhibits the differentiation of RORγ+ regulatory T cells (iTregs) in the colon. C NMU promotes NMUR-dependent ILC2 production of IL-5 and IL-13, which promotes host defense against N. braliensis infection. D CGRP downregulates IL-13 production by ILC2s, ameliorating OVA-induced allergy. E VIP suppresses IL-22 production by ILC3s in a VIPR2-dependent manner, compromising host defense against C. rodentium infection. F VIP boosts IL-22 production by VIPR2-expressing ILC3s, protecting the host from DSS colitis

Fig. 4

Sympathetic neuron regulation of gut immunity. Sympathetic neuron activation leads to the release of catecholamines, such as norepinephrine (NE), which regulates immunity. A NE inhibits the expression of MAdCAM-1 on blood vessel endothelial cells in a βAR-dependent manner, limiting immune cell extravasation during colitis; B NE enhances arginase 1 expression and polyamine synthesis in macrophages in a β2AR-dependent manner, preventing enteric neuron cell death; C NE limits IL-5 and IL-13 production by β2AR-expressing ILC2s, which weakens host defense against N. braliensis infection

Fig. 5

Parasympathetic neuronal regulation of gut immunity. Parasympathetic neurons release the neurotransmitter acetylcholine (Ach), which regulates immunity. A Ach enhances T-cell production of IL-13 and IFNγ, facilitating host defense against intestinal Salmonella and N. braliensis infections; B Ach promotes luminal antigen sampling through goblet cell-associated antigen passages (GAPs), resulting in antigen presentation by tissue CD103+ DCs