Autonomic-Immune Crosstalk in Lupus: Impaired Cholinergic Signaling and Consequences for Cardiovascular-Renal Physiology

Abstract

Over the years, our group has used complementary approaches to examine how autonomic-immune crosstalk influences the pathogenesis of systemic lupus erythematosus (SLE). We found that pharmacological enhancement of vagal activity and engagement of the parasympathetically-mediated cholinergic anti-inflammatory pathway via systemic administration of galantamine attenuated pathogenic autoantibodies, blood pressure and inflammatory mediators in murine lupus. With longer administration, galantamine also attenuated splenic B cells and renal fibrosis, and improved survival. Complementary B cell depletion studies in the same mouse model supported an important role for B-cell-dependent autoimmunity in hypertension and kidney injury in lupus, providing mechanistic context for why cholinergic anti-inflammatory pathway-targeted interventions are effective. In contrast, direct localized chemogenetic stimulation of efferent parasympathetic neurons in the dorsal motor nucleus of the vagus did not alter blood pressure or autoantibody levels but improved renal pathology in lupus mice. Similarly, bilateral denervation of renal sympathetic nerves did not affect blood pressure or autoantibody production but reduced albuminuria in lupus mice. Together, these studies demonstrate that direct modulation of autonomic nerve activity can selectively influence kidney outcomes and that a precise balance between parasympathetic and sympathetic signaling is required to maintain immune cell and inflammatory homeostasis. Disruption of this balance may contribute to chronic inflammatory diseases such as SLE and others. This review highlights emerging opportunities for cholinergic anti-inflammatory pathway-based pharmacological and neuromodulatory strategies to mitigate inflammation-driven autoimmune, cardiovascular, and renal disease.

The authors' abstract, as published at the source. American Journal of Physiology-Cell Physiology, 2026 · DOI ↗