Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Abstract

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we asked whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion led to expanded goblet and tuft cell populations. Sprouty2 loss induced PI3K/Akt signaling, leading to GSK3β inhibition and epithelial interleukin (IL)-33 expression. In vivo, this resulted in increased stromal IL-13+ cells. IL-13 in turn induced tuft and goblet cell expansion in vitro and in vivo. Sprouty2 was downregulated by inflammation; this appeared to be a protective response, as VillinCre;Sprouty2 F/F mice were resistant to DSS colitis. In contrast, Sprouty2 was elevated in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.

Orally Administered Lactobacillus rhamnosus CY12 Alleviates DSS-Induced Colitis in Mice by Restoring the Intestinal Barrier and Inhibiting the TLR4-MyD88-NF-κB Pathway via Intestinal Microbiota Modulation

“…8,40 The previous study has reported that the damage in mucosal structure and loss of goblet cells is associated with the pathological injury of colitis. 41 In this research, the AB-PAS staining results (Figure 2B,E) showed lower goblet cells in the DSS-induced mice groups than in the normal mice group (P < 0.05), while the DSS-induced goblet cells' depletion was remarkably mitigated in the LCY12 intervention groups compared to the DSS group 45−47 The dysregulated synthesis of pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8, and TNF-α, plays a critical role in both the murine model of DSSinduced colitis and individuals with IBD. 48 These cytokines serve as crucial biomarkers for various inflammatory conditions; notably, elevated levels of pro-inflammatory cytokines alongside reduced levels of IL-10 were observed in ulcerative colitis patients compared to those with Crohn's disease.…”