Interleukin-10 regulates goblet cell numbers through Notch signaling in the developing zebrafish intestine

Abstract

Cytokines are immunomodulatory proteins that orchestrate cellular networks in health and disease. Among these, interleukin (IL)-10 is critical for the establishment of intestinal homeostasis, as mutations in components of the IL-10 signaling pathway result in spontaneous colitis. Whether IL-10 plays other than immunomodulatory roles in the intestines is poorly understood. Here, we report that il10, il10ra, and il10rb are expressed in the zebrafish developing intestine as early as 3 days post fertilization. CRISPR/Cas9-generated il10-deficient zebrafish larvae showed an increased expression of pro-inflammatory genes and an increased number of intestinal goblet cells compared to WT larvae. Mechanistically, Il10 promotes Notch signaling in zebrafish intestinal epithelial cells, which in turn restricts goblet cell expansion. Using murine organoids, we showed that IL-10 modulates goblet cell frequencies in mammals, suggesting conservation across species. This study demonstrates a previously unappreciated IL-10-Notch axis regulating goblet cell homeostasis in the developing zebrafish intestine and may help explain the disease severity of IL-10 deficiency in the intestines of mammals.

Characteristics of mucin hypersecretion in different inflammatory patterns based on endotypes of chronic rhinosinusitis

“…IL-10 prevents protein misfolding via STAT1 and STAT3 signal transduction pathways, and thereby maintains mucin production in goblet cells and integrity of the mucus barrier (Figure 2). 102,103 IL-10sensitized mice display increased mucin production in airway epithelium after infection with RSV. 104,105 Lee et al 106 demonstrated that IL-10 can induce goblet cell proliferation and enhance mucin gene expression to induce airway diseases in transgenic mice with overexpression of IL-10 in the lungs.…”

“…(8) IL‐10 induces Muc2 gene expression through activation of JAK2/STAT1/STAT3 signaling pathway. 102 , 103 IL‐10 can indirectly induce MUC5AC secretion by enhancing the inflammatory process of IL‐13. 106 …”

“…IL‐10 prevents protein misfolding via STAT1 and STAT3 signal transduction pathways, and thereby maintains mucin production in goblet cells and integrity of the mucus barrier (Figure 2 ). 102 , 103 IL‐10‐sensitized mice display increased mucin production in airway epithelium after infection with RSV. 104 , 105 Lee et al.…”

Inflammation in Development and Aging: Insights from the Zebrafish Model

“…Zebrafish Notch signaling was described to be involved in larval zebrafish heart regeneration [81] and in the establishment of arterial system development and arterialvenous identity [88]. The Notch pathway controls cell fate decisions during embryonic development [89,90]; activation of Notch is required for initiating endothelial cell and Hemogenic Endothelium formation in the dorsal aorta [91] and for regulating goblet cell numbers in the developing zebrafish intestine [92].…”

Identification and Expression Analysis of IL-10 Family in Spotted Sea Bass (Lateolabrax maculatus)

“…Edwardsiella tarda, a common pathogen that can cause edwardsiellosis, is a Gram-negative bacterium that can affect a wide range of hosts, including aquatic animals, amphibians, reptiles, and mammals [24][25][26]. The IL-10 family members are essential for maintaining creaturely homeostasis and provide effective protection against microbial infection [27][28][29][30]. However, studies on these immune-related genes of spotted sea bass are not enough.…”