Luteolin ameliorates ulcerative colitis in mice via reducing the depletion of NCR⁺ILC3 through Notch signaling pathway

Abstract

The disorder of group 3 innate lymphoid cells (ILC3) subgroup, such as the predominance of NCR^-ILC3 but the depletion of NCR⁺ILC3, is unfavorable to damaged intestinal barrier repair, which leads to the prolongations and obstinacy of ulcerative colitis (UC). Our previous studies had shown that luteolin promoted NCR⁻ILC3 differentitating into NCR⁺ILC3 to improving the depletion of NCR⁺ILC3 in UC mice, while the mechanism is unclear. This article aimed to explore the underlying mechanism of luteolin enhancing the proportion NCR⁺ILC3. UC mice model was established with 2% DSS and Notch signaling was blocked, then luteolin was used to intervene. The results showed that the effect of luteolin on ameliorating disease symptoms in UC mice, including inhibiting the weight loss, reducing the pathological damage of colon mucosa, etc., was diminished with blocking Notch signaling pathway. In addition, luteolin increased the proportion of NCR⁺ILC3, NCR⁺MNK3 and IL-22⁺ILC3, decreased intestinal permeability, promoted mucin secretion, and promoted ZO-1 and Occludin expression, the above effect of luteolin was neutralized by Notch inhibitor LY-411575. Luteolin activated the abnormally blocked Notch signaling pathway in UC mice. And molecular docking predicted the affinity of luteolin for RBPJ to be −7.5 kcal·mol⁻¹ in mouse, respectively; the affinity of luteolin for Notch1 and RBPJ was respectively scored to be −6.4 kcal·mol⁻¹ and −7.7 kcal·mol⁻¹ homo sapiens. These results proved that luteolin is positive for enhancing the proportion of NCR⁺ILC3 via Notch signaling, and it provides a basis for targeting NCR⁺ILC3 for restoring intestinal barrier function to alleviating ulcerative colitis.

Keywords

Luteolin / Ulcerative colitis / Group 3 innate lymphoid cells / Notch1 / RBPJ

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Funding

National Natural Science Foundation of China(82074092)

Natural Science Foundation of Guangdong Province(2021A1515012219)

Guangzhou University of Chinese Medicine “Double First-Class” and High-level University Discipline Collaborative Innovation Team Project(2021xk81)