PVNOXT regulates acinar cell-mediated inflammatory response via DMVACh projections to the acinar cell.

The central nervous system regulates glandular secretions by modulating visceral organ functions. However, the anatomical and functional connections between the brain and digestive enzyme-producing pancreatic acinar cells remain poorly defined. Using the hypertriglyceridemia-associated acute pancreatitis (HTGP) mouse model, we aimed to describe a functional transneuronal circuit connecting the hypothalamus to pancreatic acinar cells in mice. This circuit originates from a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVNOXT), and reaches the exocrine pancreas via acetylcholinergic neurons in the dorsal motor nucleus of the vagus (DMVACh) to innervate acinar cells. Silencing of PVNOXT neurons suppresses digestive enzyme secretion and inhibits the inflammatory response in HTGP. Conversely, stimulation of these neurons induces inflammation by dysregulating secretory pathways in acinar cells. Single-cell RNA sequencing revealed that WD repeat and FYVE domain-containing 1 (Wdfy1), a gene expressed in the OXT neuron subpopulation, plays a critical role in the acinar cell-mediated inflammatory response, and its function is essential for the PVNOXT-DMVACh axis.