Fig. 1: Synergy between the mucosal immune system, the nervous system and the brain.

1) Neuronal sensing of the mucosal environment: what do neurons sense in mucosae and skin, and how do they impact immunity? Neurons can sense nutrients and microbiota directly, or receive information from immune, epithelial or stromal cells. 2) Microbiota and mucosa to brain communication: how is information conveyed from mucosae to the central nervous system? Several neuronal routes link the enteric nervous system to the brain. Information also reaches the brain through the blood and is sensed by the choroid plexus, transferred to the cerebrospinal fluid and sensed by circumventricular organs, or transferred to the brain parenchyma and sensed by microglia, and eventually collected by meningeal lymphatics. Such information transfer is involved in homeostasis, but may also be involved in the genesis of neuropathologies. 3) Brain encoding of immunological information: does the brain memorize information from microbiota and immunity, and therewith modify subsequent immune responses? The brain may encode an “immunological homunculus”, instructed by the immune system, as well as by internal and external information collected by the nervous system. An immunological homunculus would regulate subsequent immune responses. 4) Neuronal control of immune responses: to what (quantitative and qualitative) extent are local neurons and neuronal fibers involved in immune responses? Neuronal fibers at mucosae can autonomously release neurotransmitters and neuropeptides to regulate immune responses locally and rapidly spread information to the broader microregion. The local nervous system also receives information from the spinal cord and the brain, via autonomous feedback loops, or instructed by central memory. 5) A common language: do molecules involved in communication in both the nervous and the immune systems reflect common functions? Different communication modalities familiar to immunologists are also key in the development and function of the nervous system. This common language may be key to the crosstalk between the two systems, during homeostasis, as well as during pathogenesis. (This figure has been created by Matthew Macowan, Monash University, Melbourne, Australia).