Cellular Organization of Neuroimmune Interactions in the Gastrointestinal Tract

Abstract

The gastrointestinal (GI) tract is the largest immune organ; in vertebrates, it is the only organ whose function is controlled by its own intrinsic enteric nervous system (ENS), but it is additionally regulated by extrinsic (sympathetic and parasympathetic) innervation. The GI nervous and immune systems are highly integrated in their common goal, which is to unite digestive functions with protection from ingested environmental threats. This review discusses the physiological relevance of enteric neuroimmune integration by summarizing the current knowledge of evolutionary and developmental pathways, cellular organization, and molecular mechanisms of neuroimmune interactions in health and disease.

An Intestinal Organ Culture System Uncovers a Role for the Nervous System in Microbe-Immune Crosstalk

“…The interest in intestinal neuro-immune interactions and their relations with the microbiota is rapidly increasing (Margolis et al, 2016). Yet, little is known about how nociceptor neurons sense signals from the gut microbiota (Baral et al, 2016).…”

Neuro-immune regulation of mucosal physiology

“…The GI tract may be seen as a dynamic barrier that discriminates between beneficial commensals and pathogens, and that screens ingested material allowing for nutrients to be absorbed while excluding toxic substances. 8 In addition, the digestive tract exerts a large range of functions, including digestion, absorption, motility, excretion, secretion and defence. These functions are partly regulated by signals arising from parasympathetic and sympathetic extrinsic neurons, which cell bodies are located within the brainstem and spinal cord, and by the intrinsic enteric nervous system (ENS), characterized by ganglionated plexus embedded in the lining of the GI wall 5,7,[9][10][11][12] (Fig.…”

ILC3s and the Willow Tree of Voices

“…In vertebrates, it is the only organ whose function is controlled by its own enteric nervous system (ENS) and is additionally regulated by extrinsic sympathetic and parasympathetic innervation. Analysis of evolution and embryonic development of intestinal nervous and immune systems suggests that the two systems are integrally involved in gut protection and points to the gut-associated lymphoid tissue (GALT) as a key immune element associated with the neural regulation (Margolis et al, 2016). Thus, common signaling pathways control the development of the ENS and GALT.…”

“…In fetal mesenteric lymph nodes, neuronal retinaldehyde dehydrogenase (RALDH) induces the retinoic acid-dependent production of the chemokine CXCL13 via stromal organizer cells followed by the clustering of lymphoid tissue inducer (LTi) cells (van de Pavert et al, 2009); similar mechanisms might also be involved in formation of Peyer's patches. Moreover, observations in patients sug-gest association of congenital intestinal aganglionosis (Hirschsprung's disease) with mucosal immunodeficiency, and mice modeling human Hirschsprung's disease have small lymphopenic Peyer's patches and gut-specific deficiency in secretory IgA (Margolis et al, 2016).…”

“…Together with the finding that vagal efferent stimulation upregulates CXCL13 production in the mouse ileum (van de Pavert et al, 2009), this suggests that extrinsic innervation to the gut regulates trafficking of B cells in the mucosa, which might be required for their rapid mobilization during infection. Additionally, a specialized subset of intestinal macrophages closely associated with the ENS has recently received attention; macrophage numbers within the ENS are controlled by enteric neurons through secretion of colony stimulatory factor 1 (CSF1), also known as macrophage colony stimulatory factor (M-CSF) (Margolis et al, 2016), and their function is directly regulated by the sympathetic nervous system (Gabanyi et al, 2016). In the skin, nociceptive sensory neurons have been shown to drive inflammatory cytokine IL-23 production by resident phagocytes (Riol-Blanco et al, 2014).…”