RT Journal Article
SR Electronic
T1 Macrophages-induced IL-18–mediated eosinophilia promotes characteristics of pancreatic malignancy
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000979
DO 10.26508/lsa.202000979
VO 4
IS 8
A1 Hemanth Kumar Kandikattu
A1 Murli Manohar
A1 Alok Kumar Verma
A1 Sandeep Kumar
A1 Chandra Sekhar Yadavalli
A1 Sathisha Upparahalli Venkateshaiah
A1 Anil Mishra
YR 2021
UL https://www.life-science-alliance.org/content/4/8/e202000979.abstract
AB 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.