Anti-inflammatory Cholinergic Signals Inhibit Islet Resident Macrophage Responses to ATP in Living Pancreatic Tissue Slices

When stimulated by high glucose concentrations, beta cells release ATP together with insulin. Under these conditions, the ATP concentration in the islet reaches levels that would induce inflammatory responses in other tissues. Yet inflammation does not occur during normal islet physiology. We therefore postulated that there is a local anti-inflammatory circuit that prevents pathological immune responses. Our studies focused on resident macrophages, which are the local immune cells in the pancreatic islet. We recently showed that islet macrophages detect ATP to gauge the level of beta cell activation. We hypothesized that the potentially inflammatory responses to ATP are inhibited in macrophages by cholinergic input from parasympathetic nerves, as reported for other organs. Using immunohistochemistry, we found that most islet resident macrophages were indeed contacted by local cholinergic nerves, with an innervation density that was equivalent to that of beta cells. To study the impact of local cholinergic nerves on resident macrophages, we used living tissue pancreatic slices, where activity of islet cells, nerves, and macrophages can be visualized in a preserved local microenvironment. We determined that Ca2+ responses to ATP were inhibited in islet macrophages by nicotine, an agonist of nicotinic acetylcholine receptors. These results indicate that macrophages receive cholinergic input from parasympathetic nerves. We expect our studies to identify parasympathetic nerves as a source of anti-inflammatory signals that efficiently dampen the potentially pro-inflammatory environment in the islet.