Autophagy Induced FHL2 Upregulation Promotes IL-6 Production by Activating the NF-κB Pathway in Mouse Aortic Endothelial Cells after Exposure to PM2.5.

Wen-Rong Xia,Dong-Gang Xu,Dong-Qun Xu,Qin Wang,Wenliang Fu,Min Wang,Xiaoming Zhu,Wei-Wei Xing

doi:10.3390/ijms18071484

Abstract

Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with cardiovascular morbidity and mortality, which share the common feature of PM2.5-induced vascular inflammation; however, the underlying mechanisms of how PM2.5 triggers increased inflammatory response in vascular endothelial cells are not well understood. After treating mouse aortic endothelial cells (MAECs) with different concentrations of PM2.5, we assessed interleukin (IL)-6 and four and a half LIM domains 2 (FHL2) expression in cell supernatant by enzyme-linked immunosorbent assay and Western blot, respectively, as well as activation of nuclear factor (NF)-κB and immune-response signaling pathways. Additionally, changes in pathway activation, IL-6 expression, and autophagy were evaluated under PM2.5 exposure, following FHL2 knockdown with small interfering RNA. Our results indicated that PM2.5 exposure induced FHL2 expression and IL-6 secretion, as well as activation of pathways associated with immune response. Additionally, following FHL2 knockdown, the activation of NF-κB-related pathways and IL-6 secretion was inhibited under PM2.5 exposure, although the Akt- and p38-signaling pathways were not affected. Furthermore, PM2.5 exposure induced autophagy, whereas autophagy inhibition eventually inhibited PM2.5-induced FHL2 expression. These findings suggested a novel link between autophagy induced FHL2 upregulation and IL-6 production in MAECs under PM2.5 exposure.

Highlights

Epidemiological and clinical studies increasingly show that exposure to particulate matter with an aerodynamic diameter ≤ 2.5 μm (PM2.5) constitutes a risk factor associated with cardiovascular morbidity and mortality [1]
VInCflAamM-m1 atory injury in rat lungs exposed to PM2.5 and SO2 is associated with p38/nuclear factor (NF)-κB-signaling pathway activation [26], and PM2.5-induced oxidative stress increases intercellular adhesion molecule 1 (ICAM-1) and vascular cellular adhesion molecule 1 (VCAM-1) expression in human endothelial cells via an eadndexthtraat cPeMll2u.5laalrsosipgrnomaloitnedg pk6i5naansde (ERK)/Akt/NF-κB-dependent pathway [27]
Recent studies showed that signaling related to Akt, ERK, NF-κB, and p38 is activated, and results in PM2.5-induced alterations in inflammatory responses

Summary

Introduction

Epidemiological and clinical studies increasingly show that exposure to particulate matter with an aerodynamic diameter ≤ 2.5 μm (PM2.5) constitutes a risk factor associated with cardiovascular morbidity and mortality [1]. Cohort studies found that risk of cardiovascular events is associated with increased blood levels of inflammatory cytokines, and that PM2.5 is a promoter of systemic inflammation and increased circulating levels of inflammatory cytokines [2,3,4]. Endothelial cells that form new blood vessels play an important role in the pathophysiology of cardiovascular diseases [7]. FHL2 plays an important role in regulating inflammation, angiogenesis, and the cardiovascular system. FHL2 promotes activation of nuclear factor (NF)-κB in gastric cancer, liver regeneration, and liver cancer [9,10], and upregulated FHL2 expression in human liver samples is significantly associated with increased inflammatory response and liver cirrhosis [11]. FHL1–3 participate in the phosphorylation of mothers against decapentaplegic homolog-2, which activates the inflammatory response through the mitogen-activated protein kinase signaling pathway [12]

Methods

Results

Conclusion