The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Geou-Yarh Liou, Ligia Bastea, Alicia Fleming, Heike Döppler, Brandy H. Edenfield, David W. Dawson, Lizhi Zhang, Nabeel Bardeesy, Peter Storz
The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM]), which then gives rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly decreased the accumulation of alternatively activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

Graphical abstract

Teaser

Liou et al. show that PanIN and Tuft cells produce IL-13 and that the presence of IL-13 at early pancreatic lesions leads to the accumulation of alternatively activated macrophages. Alternatively activated macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrosis and lesion growth.


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