Mechanisms of pancreatic inflammation in obesity

Columbia University Health Sciences, New York NY

Investigators

Abstract

PROJECT SUMMARY Obesity produces a chronic pro-inflammatory state, and increases the risk for inflammation driven pancreatic diseases, most notably acute pancreatitis, and pancreatic cancer. The exocrine pancreas contains a high density of specialized macrophages and T cells that interact together, but little is understood about how obesity affects pancreas immune cells and their role in driving pancreatic inflammation. We therefore investigated how obesity affects pancreatic immune cells. Body mass index, a marker of adiposity, correlates with the density of TRMs in the exocrine pancreas. Obese pancreas also shows a higher proportion of pro-inflammatory macrophages expressing CD11c which interact with and increase T cell activation. Deeper analysis with single cell sequencing revealed that macrophages with signatures of embryonic origin have strong pro-repair functions, while those derived from bone marrow monocytes upregulate CD11c and show pro-inflammatory properties. This suggests that during obesity, monocyte- derived macrophages may contribute to inflammation, while embryonic macrophages attempt to maintain tissue homeostasis. To test this hypothesis, we propose two specific aims. In aim 1 we will investigate how the origin of pancreatic macrophages (embryonic vs. monocyte-derived) affects their function in obesity. We hypothesize that monocyte-derived macrophages, differentiating in obese pancreas, are more pro- inflammatory than embryonic macrophages or those found in lean individuals. To test this, we will isolate and compare the macrophage lineages from obese and non-obese organ donors and analyze their cytokine production and ability to activate T cells. Additionally, a mouse model will be used to track and compare these macrophage populations in lean and obese mice. This will ultimately reveal the source of pro- inflammatory macrophages during obesity. In aim 2 we will explore how monocyte-derived macrophages contribute to pancreatic inflammation in obesity. We hypothesize that these macrophages exacerbate inflammation and disrupt the normal function of embryonic macrophages. To test this hypothesis, we will perform multiplex staining and immune spatial profiling of obese and non-obese human pancreas to quantify the interactions of embryonic and monocyte derived macrophages with T cell rich inflammatory foci that appear during obesity. Furthermore, a mouse model for the selective depletion of monocyte-derived macrophages will be developed. This model will be used to study how depleting these macrophages affects immune regulation and T cell interactions within the pancreas of obese mice. This research leverages human data and mouse models for a deeper understanding of pancreatic macrophage origin, and function during obesity, and their role in pancreatic inflammation. By addressing this critical knowledge gap, the study holds promise for developing novel therapeutic strategies that target macrophages to prevent or treat obesity-associated pancreatic diseases.