Luteolin Regulates the Differentiation of Regulatory T Cells and Activates IL-10-Dependent Macrophage Polarization against Acute Lung Injury.

Ke Xie,Shi-Hui Lin,Chuan-Jiang Wang,Yu-Sen Chai,Fang Xu,Youmin Kang

doi:10.1155/2021/8883962

Abstract

Objectives Inflammatory disease characterized by clinical destructive respiratory disorder is called acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Studies have shown that luteolin exerts anti-inflammatory effects by increasing regulatory T cells (Tregs). In this study, we aimed to determine the effects of luteolin on ALI/ARDS and Treg differentiation. Methods In this paper, we used cecal ligation puncture (CLP) to generate an ALI mouse model to determine the effects of luteolin on ALI/ARDS. Lung tissues were stained for interleukin- (IL-) 17A and myeloperoxidase (MPO) by immunohistochemical analysis. The levels of Treg-related cytokines in serum and bronchoalveolar lavage fluid (BALF) of mice were detected. The protein levels of NF-κB p65 in lung tissues were measured. Macrophage phenotypes in lung tissues were measured using immunofluorescence. The proportion of Tregs in splenic mononuclear cells and peripheral blood mononuclear cells (PBMCs) was quantified. Furthermore, in vitro, we evaluated the effects of luteolin on Treg differentiation, and the effects of IL-10 immune regulation on macrophage polarization were examined. Results Luteolin alleviated lung injury and suppressed uncontrolled inflammation and downregulated IL-17A, MPO, and NF-κB in the lungs of CLP-induced mouse models. At this time, luteolin upregulated the level of IL-10 in serum and BALF and the frequency of CD4+CD25+FOXP3+ Tregs in PBMCs and splenic mononuclear cells of CLP mice. Luteolin treatment decreased the proportion of M1 macrophages and increased the proportion of M2 macrophages in lungs of CLP-induced mouse models. In vitro, administration of luteolin significantly induced Treg differentiation, and IL-10 promoted the polarization of M2 macrophages but reduced the polarization of M1 macrophages. Conclusions Luteolin alleviated lung injury and suppressed uncontrolled inflammation by inducing the differentiation of CD4+CD25+FOXP3+ Tregs and upregulating the expression of IL-10. Furthermore, the anti-inflammatory cytokine IL-10 promoted polarization of M2 macrophages in vitro. Luteolin-induced Treg differentiation from naïve CD4+ T cells may be a potential mechanism for regulating IL-10 production.

Highlights

Acute respiratory distress syndrome (ARDS) is a clinically devastating respiratory disorder [1, 2]
We found luteolin treatment significantly increased the proportion of Tregs in the cecal ligation puncture (CLP)-induced mouse model (Figures 2(a) and 2(b))
The results showed that the proportion of Tregs in splenic mononuclear cells and the level of IL-10 in serum decreased after CD25 neutralization

Summary

Introduction

Acute respiratory distress syndrome (ARDS) is a clinically devastating respiratory disorder [1, 2]. Even though clinical management and treatment have improved recently, the mortality rate of severe ARDS remains approximately 46.0% [3]. One of the most promising pharmacological approaches for treating ARDS is based on the pathophysiology of ARDS, i.e., the injury of alveolar epithelial and endothelial cells. Studies have shown that molecular mechanisms underlying the inflammatory responses are critical to the development of ARDS. In the control and treatment of diseases, it is necessary to adjust and control immune cells and lung microenvironment in a timely manner [4]. Current research studies focus on the identification of drugs for the treatment of ARDS. Personalized pharmacologic therapy for ARDS is one of the most promising ways to treat this disorder [5]

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