Neural reflexes in inflammation and immunity

Abstract

The mammalian immune system and the nervous system coevolved under the influence of infection and sterile injury. Knowledge of homeostatic mechanisms by which the nervous system controls organ function was originally applied to the cardiovascular, gastrointestinal, musculoskeletal, and other body systems. Development of advanced neurophysiological and immunological techniques recently enabled the study of reflex neural circuits that maintain immunological homeostasis, and are essential for health in mammals. Such reflexes are evolutionarily ancient, dating back to invertebrate nematode worms that possess primitive immune and nervous systems. Failure of these reflex mechanisms in mammals contributes to nonresolving inflammation and disease. It is also possible to target these neural pathways using electrical nerve stimulators and pharmacological agents to hasten the resolution of inflammation and provide therapeutic benefit.

Figure 1.

Humoral, cellular, and neural regulation of nonresolving inflammation. Nonresolving inflammation mediates the pathogenesis of many major diseases. Understanding mechanisms that reverse or prevent nonresolving inflammation has important implications for the development of therapeutics. Humoral and cellular antiinflammatory mechanisms are perhaps the most widely studied, and are covered in detail in other reviews. As reviewed here, recent advances in neuroscience and immunology have identified neural circuits that modulate the immune system. Understanding these circuits will reveal mechanisms for the localized and rapid control of immunity with significant therapeutic implications.

Figure 2.

The inflammatory reflex. The prototypical reflex circuit regulating immunity is comprised of afferent and efferent signals transmitted in the vagus nerve in response to the molecular products of infection and injury, including cytokines, eicosanoids, DAMPs, and PAMPs. The activation of adrenergic neurons in the spleen culminates in the release of norepinephrine in the vicinity of T cells that are capable of secreting acetylcholine. Acetylcholine crosses the marginal zone and enters the red pulp, where it interacts with α7 nAChR expressed on cytokine producing macrophages. α7 nAChR signal transduction suppresses the synthesis and release of TNF, IL-1, IL-18, HMGB1, and other cytokines.

Figure 3.

Gateway reflex. Neural signals arising from soleus muscle contractions travel to the brain stem, and then descend into the sympathetic chain to the lumbar 5 level. This regulates the activity of adrenergic neurons that modulate the expression of CCL20 by endothelial cells, providing a crucial control mechanism that gates the entry of pathogenic T cells into the CNS.

Figure 4.

Neural influence on B cell trafficking and antibody secretion. (A) Stimulation of vagus nerve signals stimulates the adrenergic splenic nerve. This leads to accumulation of CD11⁺ B cells in the marginal zone and decreased antibody production. (B) In the setting of diminished signaling from the vagus nerve to splenic nerve, antibody-secreting CD11b⁺ cells traverse the marginal zone and enter the red pulp, where they release antibodies into the circulation.