Physiology and immunology of the cholinergic antiinflammatory pathway

Abstract

Cytokine production by the immune system contributes importantly to both health and disease. The nervous system, via an inflammatory reflex of the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death. The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway. Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases. Stimulation of the vagus nerve prevents the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes. Herein is a review of this physiological, functional anatomical mechanism for neurological regulation of cytokine-dependent disease that begins to define an immunological homunculus.

Figure 1. The cytokine theory of disease.

Health requires that cytokine production is balanced: low levels are required to maintain homeostasis. Overproduction of some cytokines causes diseases that span the range of severity from mild to lethal. Some diseases can develop as a result of several different cytokines, as occurs, for example, in arthritis, which can be mediated by TNF, IL-1, or HMGB1. Other diseases may be specifically caused by individual cytokines, as occurs, for instance, in acute septic shock, with lethal hemorrhagic tissue injury mediated by an overproduction of TNF.

Figure 2. Wiring of the cholinergic antiinflammatory pathway, which balances cytokine production.

Pathogens as well as ischemia and other forms of injury activate cytokine production, which normally restores health. If the cytokine response is unbalanced or excessive, however, then these same mediators can cause disease. Efferent signals from the vagus nerve, which can be controlled by brain networks, inhibit cytokine production via pathways dependent on the α7 subunit of the AChR on macrophages and other cells. Efferent vagus nerve activity also increases instantaneous heart rate variability. A cholinergic brain network that is responsive to M1 agonists can increase the activity of the cholinergic antiinflammatory pathway and also increase instantaneous heart rate variability. Afferent signals carried in the vagus nerve can activate an efferent response that inhibits cytokine release, termed the inflammatory reflex.

Figure 3. Cholinergic signaling mediated by α7 nAChR in cytokine-producing cells.

Cholinergic signals derived from vagus nerve stimulation inhibit the release of TNF, IL-1, HMGB1, and other cytokines by transducing a cellular signal that inhibits the nuclear activity of NF-κB. TNFR, TNF receptor. Modified with permission from Nature Medicine (27).

Figure 4. The immunological homunculus.

The CNS is organized somatotopically, such that specific neural networks regulate or coordinate particular actions in the periphery. Advances in neuroimaging and neuroscience have made it possible to study this neural organization in humans. Knowledge about the cholinergic antiinflammatory pathway as a specific regulator of cytokine responses makes it possible to consider whether there is somatotopic organization to CNS regulation and coordination of the behavior of the immune system. It is plausible that this control extends beyond the simple regulation of cytokines. In the future, it may be possible to map specific brain regions that control other immune responses as depicted in this artistic rendition.