Type 1 Diabetes (T1D) is characterized by autoimmune destruction of insulin-producing beta cells within the pancreatic islets. Resident macrophages in the islets play a key role in maintaining tissue homeostasis but can also promote inflammation. The cholinergic anti-inflammatory reflex, known to suppress inflammation, may influence islet macrophages, but direct cholinergic innervation has not been established. This project aims to determine whether local cholinergic innervation suppresses islet macrophage activation.
Based on preliminary data showing that (a) islet macrophages are densely innervated by cholinergic nerves and (b) cholinergic stimuli dampen macrophage responses to ATP in living pancreatic slices, we hypothesize that cholinergic input prevents islet macrophages from transcribing proinflammatory cytokines through stimulation of nicotinic acetylcholine receptors. Using technological platforms we developed to investigate macrophages and stimulate local cholinergic neurons in the pancreas in situ we will pursue two aims: (1) Determine the immunomodulatory effects of cholinergic input on islet macrophages in the mouse and human pancreas and (2) Determine anatomical and functional changes in cholinergic control of islet macrophages in living human pancreatic slices at different stages of islet autoimmunity. Although macrophages are thought to play an important role in autoimmune initiation of T1D, we do not know how neural control of this cell population changes during T1D development. For these reasons, we will compare macrophage responses to cholinergic modulators in islets from Aab−, non-diabetic (control) donors with those in single Aab+ (GADA+; “stage 0”) and recent onset T1D organ donors (stage 3) using time-lapse confocal microscopy and living pancreas slices.
We anticipate completion of this project to provide necessary knowledge for future clinical interventions based on vagus nerve electrical stimulation for treating diabetes. In future proposals we will extend these studies to investigate cholinergic modulation of islet macrophages in living human tissue slices.