circDCBLD2 regulates the Th1/Th2 immune balance via the miR-26a-5p/PTEN axis

Abstract

Asthma is a prevalent chronic respiratory disease in children. Recently, adjusting the Th1/Th2 imbalance has become a significant focus in asthma immunotherapy. The present study aims to investigate the roles and mechanisms of circDCBLD2 in maintaining the Th1/Th2 immune balance. CircDCBLD2 is downregulated in CD4+ T cells from asthmatic patients and in CD4+ T cells from an OVA-induced asthmatic mouse model. Additionally, circDCBLD2 levels are significantly decreased in the PBMCs of asthmatic mice. The expression of circDCBLD2 is positively correlated with the Th1 cytokines IFN-γ and IL-2 but negatively correlated with the Th2 cytokines IL-4 and IL-13. Flow cytometry and ELISA analyses demonstrate that circDCBLD2 overexpression increases the proportion of Th1 cells (CD4+IFN-γ+) and the levels of Th1 cytokines while decreasing the proportion of Th2 cells (CD4+IL-4+) and the levels of Th2 cytokines. Furthermore, circDCBLD2 overexpression alleviates the asthma phenotype in OVA-induced mice, reduces the infiltration of inflammatory cells in the lungs, and corrects the Th1/Th2 imbalance. Mechanistically, circDCBLD2 is found to target miR-26a-5p. Rescue experiments indicate that circDCBLD2 regulates the Th1/Th2 immune balance by targeting miR-26a-5p. Additionally, PTEN has been identified as a direct target of miR-26a-5p. The overexpression of PTEN partially reverses the effects of miR-26a-5p on the Th1/Th2 immune balance. These findings indicate that circDCBLD2 increases the proportion of Th1 cells and decreases the proportion of Th2 cells via the miR-26a-5p/PTEN axis, providing a promising target for asthma treatment.

1. Introduction

Asthma is one of the most prevalent chronic respiratory diseases in children [1]. It is characterized by airway inflammation, reversible airway obstruction, and airway remodeling [2]. In recent years, the incidence of asthma among children has steadily increased [3]. This condition imposes a significant health and psychological burden on both children and their parents [4,5]. Currently, the primary treatments for asthma include anti-inflammatory medications and bronchodilators, such as glucocorticoids, β2 adrenergic receptor agonists, leukotriene receptor antagonists, and anti-immunoglobulin E therapies [6,7]. However, these treatments primarily alleviate symptoms rather than cure the disease. Furthermore, the prognosis for patients with asthma remains suboptimal, and there are potential toxic side effects associated with chemical medications. Therefore, further investigations into the pathogenesis of asthma and the identification of new intervention targets are highly clinically important.

The process of airway inflammation in asthma is characterized by the interaction between airway resident cells and inflammatory cells [8,9]. T lymphocytes are crucial components of the body’s immune system and play a significant role in the progression of inflammatory diseases [10]. T helper 1 (Th1) and T helper 2 (Th2) cells are two subsets of CD4+ T cells that are instrumental in the pathogenesis of asthma [11,12]. Upon exposure to external stimuli, the expression of Th2-related inflammatory factors is upregulated, whereas that of Th1-related factors is downregulated. This imbalance triggers airway hyperresponsiveness and excessive inflammation, ultimately leading to the onset of asthma [13]. Therefore, modulating the Th1/Th2 balance may be beneficial in alleviating asthma-related inflammation.

With the advancements in transcriptomics, an increasing number of studies have reported that noncoding RNAs play crucial roles in regulating the Th1/Th2 immune balance [14–16]. Circular RNAs (circRNAs) represent a newly recognized class of noncoding RNA [17,18]. Numerous reports have highlighted the involvement of circRNAs in the progression of asthma [19,20]. However, the roles of circRNAs in asthma-related Th1/Th2 immune regulation remain poorly understood.