Non-neuronal acetylcholine as a spatiotemporal autacoid in the immune and circulatory systems.

Non-neuronal acetylcholine (NNACh) operates as a spatiotemporal autacoid, functionally uncoupled from neuronal vesicular exocytosis (VAChAT/VGCC-dependent). In the immune and circulatory systems, where cholinergic innervation is relatively sparse, immune and stromal cells synthesize and release ACh autonomously to enable local immunomodulation. This review outlines NNACh's autacoid behavior, including stimulus-triggered production by ChAT+ cells, spatially constrained signaling, and rapid enzymatic degradation across lymphoid organs, visceral organs and circulatory compartments. Two regulatory modes are highlighted: (1) trafficking ChAT+ immune cells that release ACh in situ at disease sites (e.g., infection, atherosclerosis), and (2) resident immune cells adjacent to cholinergic fibers responding via non-synaptic paracrine mechanisms. Thymic tuft epithelial cells extend this framework as paracrine ACh sources mediating central tolerance. Collectively, NNACh orchestrates localized immunity through anatomically grounded, microenvironment-driven circuits. We propose therapeutic strategies: exploiting pH-sensitive AChE degradation as a spatiotemporal immune checkpoint, and lymphatic-targeted delivery to AChE-void niches (e.g., lymph nodes). This paradigm decodes microenvironment-locked cholinergic pathway, superseding neuron-centric models of immune regulation.