Tim-3 is a potential regulator that inhibits monocyte inflammation in response to intermittent hypoxia in children with obstructive sleep apnea syndrome

Abstract

The mechanism of the characteristic intermittent hypoxia (IH) of obstructive sleep apnea syndrome (OSAS) on monocyte remain unclear. Our study found that OSAS children had a significantly upregulated expression in circulating proinflammatory cytokines IL-6 and IL-12, and endothelial injury markers VEGF and ICAM1. Association analysis revealed that the plasma TNFα, IL-1β, IL-6, IL-10 and IL-12 concentration were negatively associated with the minimal SpO₂, a negative index for disease severity. OSAS monocytes presented an inflammatory phenotype with higher mRNA levels of inflammatory cytokines. Importantly, we noted a significant decrease in T-cell immunoglobulin and mucin domain (Tim)-3 expression in OSAS monocytes with the increase of the plasma proinflammatory cytokines. In vitro assay demonstrated that IH induced THP-1 cell overactivation via NF-κB dependent pathway was inhibited by the Tim-3 signal. Our results indicated that activation of monocyte inflammatory responses is closely related to OSAS-induced IH, and negatively mediated by a Tim-3 signaling pathway.

Introduction

Obstructive sleep apnea syndrome (OSAS) in children is a highly prevalent disorder caused by a conglomeration of complex pathophysiological processes, leading to recurrent upper airway dysfunction during sleep [1]. Cumulative evidence has suggested that pediatric OSAS is in fact a systemic, low-grade, inflammatory disease [2]. Intermittent hypoxia (IH) and reoxygenation, a major feature of pediatric OSAS, activates systemic inflammation that lead to collateral adverse manifestations including possible organ damages [3].While evidence suggested that inflammatory levels contracted after adenotonsillectomy or continuous positive airway pressure [[4], [5], [6]], quite a few studies revealed that some pro-inflammatory factors did not fade away and endothelial damage could not be completely avoid even after regular OSAS treatments [7,8]. Therefore, to prevent the far-reaching fallout of the chronic inflammation in OSAS children, it is particularly important to understand the underlined mechanism of IH-induced inflammation.

Of note, substantial evidence pointed to the fact that the inflammatory response of monocytes plays prominent roles in OSAS [9]. Monocytes are heterogeneous leucocytes with distinct phenotypic and functional characteristics. At least three distinct monocyte subsets exist in the blood, including classical (CD14++CD16−), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) monocyte subsets, each exerting different function by differential expression of surface and/or secreted cytokines. Changes in the monocyte subset proportion and function were shown to be closely linked with pathological alterations [10,11]. In OSAS patients and those with a number of other inflammation-related complications such as cardiovascular diseases, including atherosclerosis, hypertension and myocardial infarction, monocytes in the peripheral blood were shown to activate by the characteristic IH in the course of disease progression [12]. However, the mechanism of the IH on monocytes in OSAS children remain unclear.

We here present further assessment of the systemic inflammation by determining plasma cytokine profile in OSAS children, and scrutinizing the changes in subsets of circulating monocytes regarding their expression of soluble and surface activation markers and their relationship with disease conditions. This study aimed to reveal the cellular immune response and molecular regulatory mechanisms implicating in the maintenance of chronic inflammation in pediatric OSAS from the perspective of monocytes activation.