IL-17A–Induced PLET1 Expression Contributes to Tissue Repair and Colon Tumorigenesis

Abstract

This study identifies a novel mechanism linking IL-17A with colon tissue repair and tumor development. Abrogation of IL-17A signaling mice attenuated tissue repair of DSS-induced damage in colon epithelium and markedly reduced tumor development in AOM/DSS model of colitis-associated cancer. A novel IL-17A target gene, PLET1 (a progenitor cell marker involved in wound healing) was highly induced in DSS-treated colon tissues and tumors in an IL-17RC-dependent manner. PLET1 expression was induced in the LGR5+ colon epithelial cells after DSS treatment. LGR5+PLET1+ marks a highly proliferative cell population with enhanced expression of IL-17A target genes. PLET1 deficiency impaired tissue repair of DSS-induced damage in colon epithelium and reduced tumor formation in AOM/DSS model of colitis-associated cancer. Our results suggest that IL-17A induced PLET1 expression contributes to tissue repair and colon tumorigenesis.

Unsupervised cell interaction profiling reveals major architectural differences between small intestinal and colonic epithelial crypts

“…4c, d). Together with previous data 23 , these results support a role for Plet1+ cells in intestinal damage repair and in the maintenance of intestinal tissue integrity. It is tempting to speculate that Plet1+ crypt cells could give rise to highly motile epithelial cells that repopulate damaged epithelium.…”

“…4a), which may play a role in stemness maintenance. On the other hand, given the role of Plet1 as a marker for migratory cells [23][24][25] , an additional type of niche control such as regulating cell motility may be important.…”

“…Plet1 encodes a membrane-bound glycoprotein that plays a role in cell migration after injury [23][24][25] and that is functionally important for tissue repair upon damage of the intestinal epithelium. Differential expression analysis of Plet1+ goblet cells revealed genes with known roles in cellcell adhesion (Cgref1, Cd44, Lgals9), as well as tissue organization and inflammation (Ang, Ccl9) to be highly expressed in Plet1+ cells (Extended Data Fig.…”

The role of interleukin-17 in tumor development and progression

“…The close proximity of IL-17R and EGFR allows the adaptor protein Act1 to recruit c-Src for IL-17A-induced EGFR transactivation, enabling the activation of the MEK3-MEK5-ERK5 axis. Additionally, a substantial body of literature indicates that IL-17 stimulation is able to directly promote cell proliferation (e.g., keratinocytes and intestinal epithelial cells) by activating mitogenic signaling pathways such as ERK1/2 (Göktuna et al, 2016;Ha et al, 2014;Qian et al, 2007;Shen et al, 2009;Song et al, 2015;Wang et al, 2014;Zepp et al, 2017). Notably, ERK1/2 and ERK5 were shown to regulate distinct sets of genes (Schweppe et al, 2006).…”

“…Additionally, IL-17-induced expansion and recruitment of neutrophils are central for the control and early clearance of invasive extracellular bacteria and fungi (Cho et al, 2010;Conti et al, 2009;DeLyria et al, 2009;Khader et al, 2007;Sparber et al, 2018). Furthermore, IL-17 helps to maintain the tight junctions between intestinal epithelial cells and promote their proliferation in response to wounding (Lee et al, 2015;Zepp et al, 2017). These activities collectively ensure and enhance the barrier function of mucosal surfaces that are in direct contact with trillions of commensals.…”