Towards a nonlinear "neuroimmune gate-model": beyond stellate ganglion block and vagus nerve stimulation.

We propose a three-level neuroimmune gate model to characterize the communication between the nervous system and the immune system. The first gate, Gate 1, is the peripheral neuroimmune gate. Here, immune cells, inflammatory mediators, sensory neurons, autonomic nervous system neurons, blood vessels, and specific tissue components interact. The second gate, Gate 2, is the spinal neuroimmune gate and includes spinal afferents, spinal neurons and circuits, preganglionic sympathetic neurons, and microglia. The third gate, Gate 3, comprises supraspinal structures, including the nucleus tractus solitarii (NTS), the rostral ventrolateral medulla (RVLM), the locus coeruleus, the hypothalamus, and corticolimbic circuits. These three gates are functional centers that process and integrate inflammatory and neuronal signals dynamically and nonlinearly. This process can amplify or attenuate inflammatory reactions and disease states. The gates communicate with each other via neuronal pathways and humoral mediators. Sympathetic pro-inflammatory influences, vagal anti-inflammatory influences, and preexisting pro-inflammatory conditions (preload) are particularly important in all three gates. Unfavorable nonlinear interactions within and between these gates may cause tissue-threatening stimuli to evoke exaggerated responses, such as hyperinflammation. Understanding the three gates and their interactions can provide a conceptual framework for diagnosis and intervention. With this in mind, we will discuss the benefits of nonlinear therapeutic approaches, such as stellate ganglion blockade (SGB) and vagus nerve stimulation (VNS). We propose considering SGB and VNS as nonlinear therapeutic approaches with the capacity to close the proinflammatory neuroimmune gates based on endogenous regulatory mechanisms.