The role of type 2 innate lymphoid cells in the pathogenesis of pancreatitis
Type 2 Innate Lymphoid Cells (ILC2s) are recently discovered tissue resident immune cells, studied more commonly in barrier tissues like the lung and intestine. ILC2s are critical mediators of early type-2 immune responses and play a crucial role in the clearance of parasites, but also in the development of allergic diseases such as asthma. The function of tissue resident ILC2s in the pancreas has not been well characterised and their role in the pathology of pancreatitis remains unknown.
The inflammatory influx associated with pancreatitis has been shown to have several type 2 immune features, including eosinophilia, and considering ILC2s are potent inflammatory mediators, this project addresses the role of ILC2s in epithelial damage and organ remodelling in both acute and chronic pancreatitis.
We identified pancreatic ILC2s and characterised their physiological stimuli in the pancreas. In the caerulein mouse model of AP we found that ILC2s were activated very early, followed by a significant and persistent increase in eosinophils. Using ILC2-deficient mice we found that acute pancreatitis induced inflammation and pancreatic epithelial necrosis were significantly reduced, while immune-profiling indicated that eosinophilia was impaired. This impairment in eosinophilia was observed in ILC2-deficient mice with chronic pancreatitis as well. In acute pancreatitis, we further found that ILC2-dependent eosinophilia was also stromal cell, IL-33 and IL-5 dependent. Mouse models lacking eosinophils revealed that ILC2 dependent eosinophilia however did not regulate epithelial damage in acute pancreatitis. Thus, ILC2-driven damage was likely mediated in an eosinophil independent manner. We investigated other immune cell interactions downstream of ILC2 activation. We used genetically or therapeutically targeted depletion of neutrophils, monocytes, NK cells, T and B cells and did not find a clear mechanism. We found that ILC2 deficient mice that had chronic pancreatitis showed significantly reduced fibrosis and ADM compared to control animals during the recovery phase. However, ILC2 dependent eosinophilia did not seem to play a role in organ remodelling during the recovery phase of chronic pancreatitis either. At the recovery stage, acinar to ductal metaplasia and fibrosis were not regulated by eosinophils.
Altogether, data from this project suggests that ILC2s regulate epithelial damage and oedema in acute pancreatitis, mediate eosinophilia in acute and chronic pancreatitis and also regulate tissue remodelling in chronic pancreatitis. However, eosinophils do not play a role in regulating epithelial damage or organ remodelling during acute or chronic pancreatitis.