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Published on: November 19, 2019
Macrophages-induced IL-18-mediated eosinophilia promotes characteristics of pancreatic malignancy
Hemanth Kumar Kandikattu1, Murli Manohar1, Alok Kumar Verma1
1Department of Medicine, Tulane Eosinophilic Disorders Centre, Section of Pulmonary Diseases, School of Medicine, Tulane University, New Orleans, LA, USA.
Abstract:
Reports indicate that accumulated macrophages in the pancreas are responsible for promoting the pathogenesis of chronic pancreatitis (CP). Recently, macrophage-secreted cytokines have been implicated in promoting pancreatic acinar-to-ductal metaplasia (ADM). This study aims to establish the role of accumulated macrophage-activated NLRP3-IL-18-eosinophil mechanistic pathway in promoting several characteristics of pancreatic malignancy in CP. We report that in a murine model of pancreatic cancer (PC), accumulated macrophages are the source of NLRP3-regulated IL-18, which promotes eosinophilic inflammation-mediated accumulation to periductal mucin and collagen, including the formation of ADM, pancreatic intraepithelial neoplasia (PanINs), and intraductal papillary mucinous neoplasm. Most importantly, we show improved malignant characteristics with reduced levels of oncogenes in an anti-IL-18 neutralized and IL-18 gene deficient murine model of CP. Last, human biopsies validated that NLRP3-IL-18-induced eosinophils accumulate near the ducts, showing PanINs formation in PC. Taken together, we present the evidence on the role of IL-18-induced eosinophilia in the development of PC phenotype like ADM, PanINs, and ductal cell differentiation in inflammation-induced CP.
Insights
Accumulated macrophages drive chronic pancreatitis (CP) by activating the NLRP3-IL-18 pathway, promoting pancreatic cancer (PC) development. Targeting IL-18 reduces malignancy, suggesting a therapeutic target for PC.
Area of Science:
- Immunology
- Gastroenterology
- Oncology
Background:
- Macrophages accumulate in chronic pancreatitis (CP), contributing to its pathogenesis.
- Macrophage-derived cytokines are implicated in pancreatic acinar-to-ductal metaplasia (ADM).
Purpose of the Study:
- To investigate the role of the NLRP3-IL-18-eosinophil pathway in promoting pancreatic cancer (PC) characteristics in CP.
- To establish the mechanistic link between macrophage activation and PC development.
Main Methods:
- Utilized a murine model of pancreatic cancer (PC) and chronic pancreatitis (CP).
- Employed anti-IL-18 neutralization and IL-18 gene deficiency in murine models.
- Analyzed human pancreatic biopsies for NLRP3, IL-18, and eosinophil accumulation.
Main Results:
- Macrophages in PC models produce NLRP3-regulated IL-18, driving eosinophilic inflammation.
- This inflammation promotes ADM, pancreatic intraepithelial neoplasia (PanINs), and mucin/collagen accumulation.
- IL-18 neutralization or deficiency reduced oncogene levels and improved malignant characteristics in CP models.
- Human biopsies confirmed NLRP3-IL-18-induced eosinophil accumulation near ducts with PanINs formation.
Conclusions:
- The NLRP3-IL-18-eosinophil axis plays a critical role in promoting PC phenotypes like ADM and PanINs in inflammation-induced CP.
- IL-18-induced eosinophilia is a key driver of ductal cell differentiation and malignancy in CP.
- Targeting the IL-18 pathway presents a potential therapeutic strategy for pancreatic cancer associated with chronic pancreatitis.
