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Macrophages-induced IL-18-mediated eosinophilia promotes characteristics of pancreatic malignancy.
Life Science Alliance ( IF 3.3 ) Pub Date : 2021-06-28 , DOI: 10.26508/lsa.202000979
Hemanth Kumar Kandikattu 1 , Murli Manohar 1 , Alok Kumar Verma 1 , Sandeep Kumar 1 , Chandra Sekhar Yadavalli 1 , Sathisha Upparahalli Venkateshaiah 1 , Anil Mishra 2
Affiliation  

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.

中文翻译:

巨噬细胞诱导的 IL-18 介导的嗜酸性粒细胞增多促进了胰腺恶性肿瘤的特征。

报告表明,胰腺中积累的巨噬细胞负责促进慢性胰腺炎 (CP) 的发病。最近,巨噬细胞分泌的细胞因子与促进胰腺腺泡到导管化生 (ADM) 相关。本研究旨在确定积累的巨噬细胞激活的 NLRP3-IL-18-嗜酸性粒细胞机制通路在促进 CP 胰腺恶性肿瘤的几个特征中的作用。我们报告说,在胰腺癌 (PC) 的小鼠模型中,积累的巨噬细胞是 NLRP3 调节的 IL-18 的来源,IL-18 促进嗜酸性炎症介导的导管周围粘蛋白和胶原蛋白的积累,包括 ADM 的形成、胰腺上皮内瘤变。 PanINs)和导管内乳头状粘液性肿瘤。最重要的是,我们在抗 IL-18 中和和 IL-18 基因缺陷的 CP 小鼠模型中显示出改善的恶性特征和降低的癌基因水平。最后,人体活检证实 NLRP3-IL-18 诱导的嗜酸性粒细胞在导管附近积聚,显示 PC 中 PanINs 的形成。总之,我们提供了关于 IL-18 诱导的嗜酸性粒细胞增多在炎症诱导的 CP 中 PC 表型如 ADM、PanIN 和导管细胞分化发展中的作用的证据。
更新日期:2021-07-01
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