Editorial on the Research Topic Neuro-Immune Interactions in Inflammation and Autoimmunity The nervous system plays an important role in the regulation of immunity and inflammation ( 1 , 2 ). However, neuronal integrity and brain function may be severely altered in inflammatory and autoimmune conditions ( 3 – 5 ). Recent studies have characterized neural pathways communicating peripheral inflammatory signals to the central nervous system (CNS), and brain- and spinal cord-derived circuitries controlling various innate and adaptive immune responses and inflammation ( 1 , 2 ). A prototypical neural reflex circuit that regulates immunity and inflammation is the vagus nerve-based “inflammatory reflex” ( 6 ). Pharmacological and bioelectronic modulation of neural cholinergic circuitry in the inflammatory reflex has been successfully explored in preclinical settings of sepsis, arthritis, inflammatory bowel disease, obesity-driven disorders, diabetes, and other diseases ( 1 ). These studies paved the way to successful clinical trials in inflammatory bowel disease, rheumatoid arthritis, and metabolic syndrome ( 7 – 9 ). Dysregulated release of cytokines and other inflammatory molecules may have a severe impact on brain function ( 10 ). Brain inflammation (neuroinflammation), imbalances in brain neuronal integrity, neurotransmitter release, and cognitive impairment are characteristic features of perioperative neurological disorders, sepsis, pain, liver diseases, diabetes, and other conditions characterized by immune and metabolic dysregulation ( 3 , 11 , 12 ). These findings and the characterization of brain-reactive antibodies and neuroprotective cytokines indicated new therapeutic approaches for treating inflammatory and autoimmune disorders and their neurological complications ( 4 , 13 , 14 ). The collection of 19 papers on this research topic substantially contributes to improved understanding of neuro-immune communication and its therapeutic relevance. Yuki et al. ?elaborate on neuro-immune interactions within the gateway reflexes that regulate the entry of pathogenic CD4~(+)T lymphocytes in the CNS and neuroinflammation. They also point to the need of further characterization of the functional anatomy of these reflexes that will be of interest for their therapeutic exploration to alleviate local neuroinflammation in pathological conditions, including multiple sclerosis. Bonaz et al. review the role of the vagus nerve as a regulator of inflammatory processes in the gastrointestinal tract. They also elaborate on accumulating experimental evidence indicating possibilities to use electrical vagus nerve stimulation for therapeutic benefit in inflammatory bowel disease and other gastrointestinal disorders in preclinical and clinical settings. Innoe et al. outline new findings related to the neural vagus nerve control of inflammation with a specific focus on the kidney disease. They also summarize evidence that this neural regulation can be activated by the use of ultrasound and other modalities to alleviate inflammation and acute kidney injury in murine models. The splenic noradrenergic innervations are implicated in neuroimmunomodulation and are an important component of the inflammatory reflex through their functional cooperation with the vagus nerve. Hoover et al. provide insight into the anatomy of noradrenergic neurons in relation to leukocytes in the human spleen and experimental evidence for a significant splenic noradrenergic neuronal loss in patients who died from sepsis. These findings are of interest for further studies on the neural regulation of inflammatory processes in the spleen in the context of sepsis and other conditions. Fujii et al. present a thorough review of the cholinergic system, including choline acetyltransferase, acetylcholinesterase, acetylcholine, and muscarinic and nicotinic acetylcholine receptors in immune cells, such as macrophages, dendritic cells, and T and B lymphocytes. They also summarize findings about the functional role of this non-neuronal cholinergic system in the regulation of innate and adaptive immune responses. Valdés-Ferrer et al. evaluated the role of pyridostigmine, an acetyl-cholinesterase inhibitor, in a 16-week proof-of-concept open-label trial in HIV-infected patients with discordant immune responses. By using this strategy, the authors harnessed the cholinergic anti-inflammatory pathway and demonstrated that pyridostigmine can promote recovery of CD4~(+)T-cell counts by reducing T cell overactivation. Bosmans et al. discuss the role of cholinergic signaling, mediated through nicotinic and muscarinic receptors in the regulation of allergic inflammation, including barrier function, innate and adaptive immune responses, and effector cells responses. They also point to possibilities of exploring cholinergic regulation of type 2 immune responses in the treatment of allergic diseases. Mader et al. outline how antibodies associated with autoimmune diseases lead to br
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