Immune Cells Exploit a Neural Circuit to Enter the CNS

Abstract

Multiple sclerosis (MS) is associated with the appearance of autoreactive T cells in the central nervous system. Using a mouse model of MS, Arima et al. now show that this attack begins at a specific spinal cord location. T cell entry into the CNS is regulated by a reflex neural circuit originating from leg muscle contractions.

On October 8, 1958, Dr. Ake Senning of the Karolinska Institute in Stockholm, Sweden surgically placed the first implantable cardiac pacemaker in a 43-year-old man. Previously disabled by a potentially lethal cardiac arrhythmia syndrome, the patient went on to live a long life, to age 83, outlasting the surgeon. Since then, the medical, scientific, and science fiction communities continue to be fascinated by the clinical implications of implanting medical devices that interface with the nervous system. Indeed, device implantation is currently used for clinical problems from broken hearts to failing eyes. The prospect of using such implants to precisely control the immune system, however, is now in the offing. In this issue of Cell, Arima et al. (2012) present remarkable findings that advance this possibility by showing that neural signals transmitted along adrenergic neurons regulate the influx of activated CD4-positive T cells into the central nervous system during the onset of autoimmune disease.

To appreciate the full potential for medical devices to control immune responses, consider the example of physiological reflexes that control cardiac function. The baroreceptor reflex is activated when increases in blood pressure stimulate stretch receptors in the carotid sinuses and aortic arch, triggering action potentials that are transmitted along the vagus nerve to the brainstem and other nuclei that control outgoing pressor and depressor responses. These include decreased signaling in adrenergic nerves to the heart (reducing contractility and heart rate) and increased signaling through cholinergic neurons traveling with the vagus nerve to the heart (also reducing heart rate), thus maintaining blood pressure within a narrow homeostatic range. These long-established principles of reflex control of organ homeostasis are well known and have been widely explored in relatively accessible organs of the gastro-intestinal, skeletal muscle, and neuroendocrine systems. Less well known, however, is that recent advances over the past decade in the field of neuro-physiology have delineated similarly operating fundamental units of reflex neural action that regulate the immune system.

The inflammatory reflex is activated whenincreasing levels of inflammatory mediators from exogenous (e.g., pathogen-associated molecular pattern [PAMPs]) or endogenous (e.g., damage-associated molecular pattern [DAMPs]) molecules stimulate receptors in the vagus nerve and associated glomus cells (Figure 1, left) (Tracey, 2009). This leads to afferent action potentials being transmitted along the vagus nerve to the brainstem and other nuclei that control outgoing signals in the vagus nerve. Increased activity in the vagus to the spleen and other organs reduces the innate immune system's response to DAMPs and PAMPs, decreases the release of cytokines, and suppresses inflammation. Just as stimulating the vagus nerve can slow heart rate, so too, increasing vagus nerve activity slows innate immunity. It is important to note here that, as the inflammatory reflex circuit utilizes both the vagus nerve (classically referred to as “parasym-pathetic”) and the splenic nerve (classically referred to as “sympathetic”), it is neither sympathetic nor parasympathetic. Displaying remarkable prescience, Henry Dale, who first isolated acetylcho-line in the spleen, famously cautioned against such terminology in his 1936 Nobel Prize lecture, describing it as imprecise. More accurate description of neural circuits therefore requires terminology based on the nature of the neurotransmitters, not an inferred classification within the autonomic nervous system.

Figure 1. Neural Reflex Circuits Control Function of the Immune System.

As described in the text, the inflammatory reflex and the “gateway reflex” modulate the innate and adaptive immune responses to threat.

Now, Arima and colleagues report the discovery of a specific neural circuit that modulates the acute activity of the adaptive rather than the innate immune system (Figure 1, right). Studying the mouse model of multiple sclerosis (MS) known as experimental allergic encephalomyelitis (EAE), in which CD4-positive T cells that have been primed to attack myelinated nerves are introduced into the bloodstream, they noticed that, at the earliest stages of disease progression, autoreactive T cells cross the blood-brain barrier at a highly specific location: the fifth lumbar level of the spinal cord. Wondering why this specific point acted as a gateway for T cells, they discovered that dorsal blood vessels express high levels of the chemokine CCL20. Reasoning that the fifth lumbar vertebrae lie close to the dorsal root ganglia of sensory neurons that innervate the soleus and other leg muscles, they decided to test whether silencing this muscle-sensitive neuronal pathway would inhibit chemokine expression and pathogenic T cell entry. Incredibly, limiting contraction of the soleus muscle by simply suspending the mice by their tail was sufficient to reduce CCL20 expression and block accumulation of T cells at the gateway.

Their findings raise the possibility that a reflex circuit controls a critical step in the progression of autoimmune disease. The precise route by which skeletal muscle activity influences the vascular endothelium is not yet clear but may involve three neurons: the sensory neuron, traveling up to the brain stem; efferent cholinergic neurons descending in the sympathetic chain from the brainstem; and the adrenergic neurons that innervate the endothelial cell. A similar muscle to adrenergic neuron arrangement has been implicated in the exercise pressor reflex, a three-neuron circuit that modulates the cardiovascular response to exercise. It will be extremely important to follow the advances in further defining this neural circuitry, a “gateway reflex,” to understand the specific cell receptor targets.

Understanding of the inflammatory reflex recently took on a new twist, with the findings that the circuitry that culminates on cytokine-producing macrophages in the spleen not only requires three neurons and two neurotransmitters, but also involves an unusual role for T cells (Figure 1, left). The first neuron in the reflex is sensory, traveling in the vagus nerve to the brain stem. The second is cholinergic and travels in the vagus nerve to the celiac ganglion. The third neuron, which arises there, is adrenergic and travels in the splenic nerve to deliver norepinephrine to β2 adrenergic receptors expressed on a subset of T cells capable of secreting acetylcholine (Rosas-Ballina et al., 2011). Remarkably, T cells therefore act in place of cholinergic neurons, activating α7 nicotinic acetylcholine receptors expressed on cytokine-producing macrophages in the marginal zone and red pulp. Cholinergic signaling suppresses cytokine transcription and release by downregulating the nuclear activity of NFκB.

It is interesting to consider the therapeutic implications of the present findings by Arima and colleagues of a reflex circuit that modulates blood-brain barrier integrity. It is now plausible that implanted neurostimulating or inhibiting devices may be of therapeutic value for the treatment of neurological autoimmune disease. Knowledge of the inflammatory reflex spawned research into experimental pacemaker-like devices to stimulate the vagus nerve. These have already been shown to confer significant protection against other inflammatory disease syndromes, such as in animal models of adjuvant arthritis, inflammatory bowel disease, ischemia-reperfusion, and sepsis (Koopman et al., 2011). Pharmacological agents that target this pathway using selective agonists of α7 nAChR confer significant protection against diet-induced obesity, acute lung injury, asthma, insulitis, insulin resistance, and atherogenesis.

The molecular mechanism underlying the inflammatory circuit requires signal transduction via the α7 nAChR. The electrical signals generated by the device are relayed by neuronal signaling to the target organ and are converted there into cholinergic signals that can be also be recapitulated by administration of highly selective α7 nAChR agonists to block inflammation. Thus, whereas these devices are computerized impulse generators that create electrical signals in specific nerves, the nature of the inflammatory reflex as a neural circuit converts the electrical signal back to the pharmacological. Many epidemiologically important diseases, including those listed above, occur because inflammation fails to resolve (Nathan and Ding, 2010). Widespread clinical evidence reveals that a failure of vagus nerve signaling can contribute to this resolution failure. Vagus nerve activity is decreased in patients with autoimmune and autoinflammatory diseases, and it is quite plausible that the absence of tonic inhibitory signals in the inflammatory reflex facilitates the non-resolution of inflammation.

Whereas the reflex principles described here are prototypical and well understood, it is quite likely that additional, as yet undiscovered neurophysiological reflexes will be mapped. The findings of Arima and colleagues represent a signifi-cant advance in this field and are likely to expand interest in new mechanisms and therapeutic strategies to specifically modulate the activity of neural circuits.