The Gut's Little Brain in Control of Intestinal Immunity

Abstract

The gut immune system shares many mediators and receptors with the autonomic nervous system. Good examples thereof are the parasympathetic (vagal) and sympathetic neurotransmitters, for which many immune cell types in a gut context express receptors or enzymes required for their synthesis. For some of these the relevance for immune regulation has been recently defined. Earlier and more recent studies in neuroscience and immunology have indicated the anatomical and cellular basis for bidirectional interactions between the nervous and immune systems. Sympathetic immune modulation is well described earlier, and in the last decade the parasympathetic vagal nerve has been put forward as an integral part of an immune regulation network via its release of Ach, a system coined "the cholinergic anti-inflammatory reflex." A prototypical example is the inflammatory reflex, comprised of an afferent arm that senses inflammation and an efferent arm: the cholinergic anti-inflammatory pathway, that inhibits innate immune responses. In this paper, the current understanding of how innate mucosal immunity can be influenced by the neuronal system is summarized, and cell types and receptors involved in this interaction will be highlighted. Focus will be given on the direct neuronal regulatory mechanisms, as well as current advances regarding the role of microbes in modulating communication in the gut-brain axis.

Figure 1

The cholinergic anti-inflammatory pathway depicted. Scheme of the vagus nerve interacting with immune activation at multiple levels following ingestion, infection, and trauma. (1) During digestion, the commensal flora and dietary components activate the sensory afferent vagus nerve, which will transmit the information to the brain. In return, the brain may activate the efferent vagus nerve to modulate gastrointestinal macrophages. (2) The efferent vagus nerve also modulates systemic inflammatory responses through a mechanism involving an intact spleen. Upon infection or trauma, bacterial components or intracellular mediators (HMGB1, heat shock proteins, etc.) activate macrophages to produce proinflammatory cytokines. (3) This will trigger afferent vagus nerve signaling. (4) Central activation of vagal efferent pathways which lead to release of acetylcholine (ACh) and relay on peripheral ganglia to stimulate adrenergic transmitter release (in the spleen) to act on aplenic antigen presenting cells and macrophages. Recent data indicate the generation of ChAT-positive ACh producing immune cells (see text). Interrogation marks indicate that, although macrophages are found in the proximity of cholinergic fibers in the spleen and the intestine, there is currently no evidence demonstrating that parasympathetic neurons, indeed, innervate immune cells in the gut wall. HMGB1: high-mobility group box 1.

Figure 2

MMCP-1 in peritoneal lavage. Electrical stimulation of the vagus nerve in mice leads to decreased release of mast cell specific products in the peritoneal cavity. Shown are the levels of mouse mast cell specific protease 1 (mmcp-1) in the peritoneal cavity of mice that underwent vagal nerve stimulation of the cervical nerve 30 minutes before laparotomy control (L) or intestinal manipulation (IM) surgery. The effects of VNS depend on activation of the nAChR β2 [52], as VNS has no effect on mice deficient in this receptor. Unpublished data, S. A. Snoek, Tytgat Institute, 2012.

Figure 3

Electrical stimulation of the vagus nerve in mice leads to decreased release of proinflammatory gene products in the peritoneal cavity after surgical manipulation. Shown are the levels of mouse TNF, CCL-2, and IL-6 in the peritoneal cavity of mice that underwent vagal nerve stimulation (VNS) of the cervical nerve 3 h before laparotomy control (L) or intestinal manipulation (IM) surgery. Data are modified from [48], Tytgat Institute, 2012.

Figure 4

VIP/SP and ACh/nicotine modulate inflammatory mediators in a cumulative manner. (a) RAW peritoneal macrophages were incubated with a dose range of VIP (0–10 μM) for 30 min prior to 3 hrs LPS stimulation (100 ng/mL). TNF production was measured with ELISA. (b) cells were pretreated with 10 μM ACh/nicotine for 30 min, then stimulated with 10 μM VIP or SP, and followed by 100 ng/mL LPS challenge. TNF levels were measured after 3 hrs and depicted as % of vehicle-treated cells. Data are mean s.e.m. of three independent experiments done in triplicate. *P < 0.05; **P < 0.01. E.P. van der Zanden et al., Tytgat Institute AMC, unpublished 2012.