Interference with pancreatic sympathetic signaling halts the onset of diabetes in mice

Abstract

The notably lobular distribution of immune lesions in type 1 diabetes (T1D) has been hypothesized to be the result of innervation within the pancreas. To investigate whether neuroimmune interactions could explain this phenomenon, we explored the impact of sympathetic signaling in the RIP-LCMV-GP mouse model of autoimmune diabetes. In this model, the CD8+ T cell attack on β cells replicates a key pathogenic feature of human T1D. We found that inhibition of α1 adrenoceptors, ablation of sympathetic nerves, and surgical denervation all had a protective effect in this model, without affecting the systemic presence of β cell–reactive CD8+ T cells. In vivo multiphoton imaging revealed a local effect within pancreatic islets including limited infiltration of both macrophages and β cell–specific CD8+ T cells. Islet-resident macrophages expressed adrenoceptors and were responsive to catecholamines. Islet macrophages may therefore constitute a pivotal neuroimmune signaling relay and could be a target for future interventions in T1D.

Optical Imaging of Pancreatic Innervation

“…Sympathetic activation leads to vasoconstriction, reduces exocrine secretion, and shifts endocrine secretion to the hyperglycemic state by lowering insulin and increasing glucagon levels ( 44 , 45 ). In addition to this canonical sympathetic effect on pancreatic secretory function, several recent studies report an important interaction of sympathetic innervation with the pancreatic immune system ( 14 , 46 , 47 ), which could be involved in the development of autoimmune diabetes ( 48 ).…”

“…Perhaps investigators were not motivated to do so because of the common notion that sympathetic stimulation induces a uniform inhibitory effect on digestion. Recent studies, however, are revealing an important interaction of sympathetic nerves with the immune system, particularly with immune cells of lymph nodes associated with the pancreas ( 14 , 46 , 47 ). A characterization of postganglionic sympathetic neurons therefore becomes physiologically and even clinically relevant.…”

“…The pancreas can be partially exteriorized and imaged acutely in anesthetized animals (46,(75)(76)(77). For gaining longitudinal optical access to the pancreas, several recent studies report the use of an intravital window installed into the abdominal wall.…”

“…Pancreas exteriorization and abdominal window provide access for imaging superficial structures at cellular resolution. Although innervation has never been imaged at the level of the intact pancreas in vivo, several studies report effective imaging of pancreatic endocrine cells, immune cells, and vasculature (46,(75)(76)(77), suggesting that this approach can potentially be used for imaging superficial large neuronal structures such as pancreatic ganglia and neuroinsular complexes. However, due to limitations of optical tissue penetration and residual tissue movement, this technique is not ideally suited for imaging fine neuronal projections and terminals.…”

Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism

“…Whether pancreatic b cells have developed a mechanism for detecting these insulin fragments and initiating signaling cascades to modulate the metabolic state remains unclear. Moreover, recent evidence suggests that local proliferation of islet-resident macrophages plays a key role in islet inflammation and diabetes development (Christoffersson et al, 2020;Golden and Simmons, 2021;Ying et al, 2019Ying et al, , 2020. However, how intra-islet crosstalk regulates this process is largely unknown.…”