2103-LB: Cholinergic Innervation of the Islet Resident Macrophage

Pancreatic islets are small endocrine organs containing beta cells and alpha cells that control glucose metabolism. These cells are supported by resident macrophages that tightly maintain tissue homeostasis. Islet resident macrophages respond to ATP secreted alongside insulin by increasing inflammatory cytokine expression. Thus, the normal physiology of insulin secretion has the potential to initiate an inflammatory response that needs to be limited. We propose that the cholinergic anti-inflammatory pathway provides a neural check on this inflammation. The cholinergic anti-inflammatory pathway reduces systemic inflammation in the case of sepsis and may play a role in other inflammatory conditions. However, there is no current understanding of the innervation of islet resident macrophages. To start addressing communication between cholinergic neurons and islet macrophages, we examined macrophages in the pancreas of transgenic mice expressing the green fluorescent protein GFP under the control of the choline acetyltransferase promoter. We found that islet macrophages were densely contacted by cholinergic terminals. We further studied functional responses of islet resident macrophages in living pancreas slices from transgenic mice expressing a fluorescent Ca2+ sensor (GCaMP6) under the control of the CSF1R promoter. Ca2+ responses to ATP in these macrophages were strongly inhibited in the presence of acetylcholine or nicotinic agonists. Oxotremorine, a selective muscarinic agonist, failed to dampen the macrophage response to ATP. Our findings showing that cholinergic nerves directly innervate islet resident macrophages and that selective nicotinic agonism modulates their responses to ATP suggesting that the cholinergic anti-inflammatory pathway provides neuroimmunomodulation in normal islet homeostasis. Further characterization of this pathway seems warranted as it could be harnessed to inhibit the chronic inflammatory conditions that trigger diabetes pathogenesis. Disclosure N.Borowsky: None. A.Caicedo: n/a.