Neuro-Immune Interactions at Barrier Surfaces

Abstract

Multidirectional interactions between the nervous and immune systems have been documented in homeostasis and pathologies ranging from multiple sclerosis to autism, and from leukemia to acute and chronic inflammation. Recent studies have addressed this crosstalk using cell-specific targeting, novel sequencing, imaging, and analytical tools, shedding light on unappreciated mechanisms of neuro-immune regulation. This Review focuses on neuro-immune interactions at barrier surfaces-mostly the gut, but also including the skin and the airways, areas densely populated by neurons and immune cells that constantly sense and adapt to tissue-specific environmental challenges.

Figure 1. Neuroregulators control hematopoietic stem cells (HSC)

Neuron satellite Schwann cells, induce activation of latent TGF-β that ensures HSC quiescence. In turn, neurotrophic factors directly activate HSC via the tyrosine kinase receptor RET leading to improved HSC survival. Sympathetic nervous fibers produce norepinephrine that downregulates CXCL12 expression in mesenchymal stem cells (MSC). Reduced CXCL12 expression by MSC prompts HSC egress from the niche.

Figure 2. Neuro-immune circuits in the intestine

(1) Most of immune cells accumulate in the lamina propria of the mucosa regions while neuronal cell bodies are restricted to the submucosal and myenteric plexuses, regions populated by distinct muscularis macrophages and mucosal mast cells. Extrinsic and intrinsic neuronal processes innervate all intestinal layers. Initial sensing of luminal perturbations may be mediated by intestinal epithelial cells (IECs), innate immune cells or directly by neurons. Among several possible downstream neuro-immune circuits, four are depicted: 2- Short local neuro-immune circuit between lamina propria and muscularis immune cells and the (intrinsic and extrinsic) nervous system. 3- Vagal neuro-immune loop with afferent and efferent fibers originating within the medulla oblongata. 4- Long-range enteric-associated neuron-immune loop, with intestinofugal fibers projecting to the spinal cord or ganglion (a) or afferent and efferent fibers originating in the DRG and spinal cord, respectively (b). Red processes: afferent. Light blue processes: efferent.