Neuroimmune Communication in Health and Disease

Abstract

The immune and nervous systems are tightly integrated, with each system capable of influencing the other to respond to infectious or inflammatory perturbations of homeostasis. Recent studies demonstrating the ability of neural stimulation to significantly reduce the severity of immunopathology and consequently reduce mortality have led to a resurgence in the field of neuroimmunology. Highlighting the tight integration of the nervous and immune systems, afferent neurons can be activated by a diverse range of substances from bacterial-derived products to cytokines released by host cells. While activation of vagal afferents by these substances dominates the literature, additional sensory neurons are responsive as well. It is becoming increasingly clear that although the cholinergic anti-inflammatory pathway has become the predominant model, a multitude of functional circuits exist through which neuronal messengers can influence immunological outcomes. These include pathways whereby efferent signaling occurs independent of the vagus nerve through sympathetic neurons. To receive input from the nervous system, immune cells including B and T cells, macrophages, and professional antigen presenting cells express specific neurotransmitter receptors that affect immune cell function. Specialized immune cell populations not only express neurotransmitter receptors, but express the enzymatic machinery required to produce neurotransmitters, such as acetylcholine, allowing them to act as signaling intermediaries. Although elegant experiments have begun to decipher some of these interactions, integration of these molecules, cells, and anatomy into defined neuroimmune circuits in health and disease is in its infancy. This review describes these circuits and highlights continued challenges and opportunities for the field.

FIGURE 1.

The proposed circuitry of the cholinergic anti-inflammatory pathway. The cholinergic anti-inflammatory pathway is proposed to begin with the detection of inflammation in the periphery. This information is relayed by vagal afferent neurons to the nucleus tractus solitarius (NTS) resulting in vagal efferent (parasympathetic) outflow to sympathetic ganglia that innervate the spleen and release norepinephrine (NE). This NE activates β2-adrenergic receptor (β2AR) on choline acetyltransferase (ChAT⁺) T cells that function as signaling intermediaries causing ACh to be synthesized and released. Adjacent macrophages express the nicotinic α7-receptor (α7R), which when activated by T cell-derived ACh reduces NF-κB signaling and prevents tumor necrosis factor (TNF)-α production. The alternative sympathetic efferent arm is also depicted whereby the efferent arm comprises pre- and postganglionic sympathetic neurons independent of the involvement of parasympathetic neurons. DAMPs, danger-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; DMN, dorsal motor nucleus of the vagus.

FIGURE 2.

Vagus nerve mediation regulation of intestinal inflammation. Neural inhibition of intestinal inflammation can also occur by a vagal efferent to enteric nervous system (ENS) circuit. Activation of efferent vagus nerve activity induces activation of cholinergic neurons in the ENS and release of ACh in the intestine, blocking macrophage activation in an α7-receptor (α7R)-dependent manner. TNFα, tumor necrosis factor-α.

FIGURE 3.

Sympathetic innervation of the intestine promotes anti-inflammatory macrophage differentiation. Neuroimmune communication in the intestine requires close approximation of sympathetic axons in and macrophages in the muscularis. Activation of sympathetic innervation following infection induced release of norepinephrine (NE) from nerve terminals and induction of an anti-inflammatory macrophage gene profile. β2AR, β2-adrenergic receptor.

FIGURE 4.

A sympathetic pathway in the inhibition of systemic inflammation. C1 neurons residing in the medulla oblongata have been implicated as another coordination center that initiates descending signals to reduce immune activation. It is important to note that the immunomodulatory circuitry of this motor pathway does not require the vagus nerve. NE, norepinephrine; TNFα, tumor necrosis factor-α; β2AR, β2-adrenergic receptor; α7R, α7-receptor.