Expression of POU2F3 Transcription Factor Control Inflammation, Immunological Recruitment and Metastasis of Pancreatic Cancer in Mice.

TUFT cells have been described as strong modulators of inflammatory cells in several tissues including pancreas. TUFT cells, also known as DCLK1+ cells, are dependent of the transcriptional factor POU2F3. Several works report DCLK1+ cells in early stages of PDAC development suggesting an important role of TUFT cells in PDAC development. Therefore, we developed a mice model (PDX1-Cre;KrasG12D;Ink4afl/fl), known as PKI model, deficient or not of POU2F3. In this animal model, deficiency of POU2F3 results in the absence of TUFT cells in PDAC as expected. Although, tumor development and growth are not significantly influenced, the development of liver metastasis was almost completely inhibited in POU2F3-deficient mice. Surprisingly, the absence of metastasis was associated with a higher expression of epithelial-to-mesenchymal transition markers, but to a lower inflammatory microenvironment suggesting that inflammation influences metastasis production more than epithelial-to-mesenchymal transition in this animal model. We can conclude that POU2F3 could be a new therapeutic target for control PDAC progression.

Adipose tissue derived-factors impaired pancreatic ß-cell function in diabetes.

Inflammatory factors produced and secreted by adipose tissue, in particular peri-pancreatic adipose tissue (P-WAT), may influence pancreatic ß-cell dysfunction. Using the ZDF Rat model of diabetes, we show the presence of infiltrating macrophage (ED1 staining) on pancreatic tissue and P-WAT in the pre-diabetes stage of the disease. Then, when the T2D is installed, infiltrating cells decreased. Meanwhile, the P-WAT conditioned-medium composition, in terms of inflammatory factors, varies during the onset of the T2D. Using chemiarray technology, we observed an over expression of CXCL-1, -2, -3, CCL-3/MIP-1α and CXCL-5/LIX and TIMP-1 in the 9 weeks old obese ZDF pre-diabetic rat model. Surprisingly, the expression profile of these factors decreased when animals become diabetic (12 weeks obese ZDF rats). The expression of these inflammatory proteins is highly associated with inflammatory infiltrate. P-WAT conditioned-medium from pre-diabetes rats stimulates insulin secretion, cellular proliferation and apoptosis of INS-1 cells. However, inhibition of conditioned-medium chemokines acting via CXCR2 receptor do not change cellular proliferation apoptosis and insulin secretion of INS-1 cells induced by P-WAT conditioned-medium. Taken together, these results show that among the secreted chemokines, increased expression of CXCL-1, -2, -3 and CXCL-5/LIX in P-WAT conditioned-medium is concomitant with the onset of the T2D but do not exerted a direct effect on pancreatic ß-cell dysfunction.

Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites.

Helminth parasitic infections are a major global health and social burden. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity. Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature and we demonstrate that they undergo a rapid and extensive IL-4Rα-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3(-/-) mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Rα signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection.