DOP089 PTPN2 controls intestinal inflammation and promotes colitis-associated tumour formation via control of inflammasome activation and IL-1alpha release

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Abstract

Background: Variants in the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with Crohn's disease (CD) and ulcerative colitis (UC). We recently found that deletion of PTPN2 in macrophages promotes colitis severity, while protecting from colitis-associated tumours, but the molecular mechanisms underlying this phenotype are still elusive. IL-1α and IL-1β exert important, yet distinct, immune-modulatory function in the intestine, but their precise role during intestinal pathologies is still controversial. Here, we investigated whether IL-1α and/or IL-1β are involved in enhanced colitis and/or reduced tumour development observed in mice lacking PTPN2 in macrophages (PTPN2-LysMCre mice).

Methods: Colitis was induced in 10–12 week old PTPN2-LysMCre mice and their wild-type (WT) littermates by administration of 2% dextran-sodium sulfate (DSS) for 7 days (acute colitis), or by repeated treatment with 1.5% DSS for 7 days, followed by 10 days normal drinking water (four cycles in total, chronic colitis). For tumour induction, mice were injected with azoxymethan (AOM) at day one of each DSS cycle during chronic colitis induction. IL-1β and IL-1α were inhibited using a vaccine-based approach.

Results:In vitro, PTPN2-deficient macrophages secreted more mature IL-1β, and levels of active caspase-1 were enhanced, indicating pronounced inflammasome activity. Responsible for enhanced inflammasome activation was increased phosphorylation of the inflammasome-adaptor molecule ASC. Further, PTPN2-deficient macrophages secreted increased levels of IL-1α, while surface-associated IL-1α was markedly reduced. As expected from our previous studies, PTPN2-LysMCre mice suffered from pronounced colitis, but reduced tumour load. In the serum, IL-1α and IL-1β levels were enhanced in PTPN2-LysMCre mice upon DSS or AOM/DSS treatment, but surface IL-1α on macrophages and intestinal epithelial cells was reduced. Inhibition of IL-1β during colitis induction/tumour formation protected PTPN2-LysMcre mice from pronounced colitis, but re-established the susceptibility to colitis-associated tumours. In contrast, inhibition of IL-1α did not affect colitis severity, while protecting WT mice from the induction of colitis-associated tumours.

Conclusions: PTPN2 is a crucial regulator of inflammasome activation, and its loss in macrophages has important consequences for intestinal homeostasis. Further, our results demonstrate that the structurally related molecules IL-1α and IL-1β exert distinct roles during intestinal inflammation and tumorigenesis, and PTPN2 modulates secretion and surface expression of these two cytokines.

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