PM2.5 exposure increases dry eye disease risks through corneal epithelial inflammation and mitochondrial dysfunctions

Abstract

Dry eye disease (DED) is the most common disease affecting vision and quality of life. PM2.5 was a potential risk of DED. Herein, we conducted animal exposure and cell-based studies to evaluate the pathogenic effect of PM2.5 exposure on the ocular surface and DED etiological mechanisms. C57 mice were exposed to filtered air and PM2.5 aerosol. We assessed health conditions and inflammation of the ocular surface by corneal fluorescein staining and immunohistochemistry. In parallel, cultured human corneal epithelial cells (HCETs) were treated with PM2.5, followed by characterization of cell viability, intracellular ATP level, mitochondrial activities, and expression level of DED relevant mRNA and proteins. In mice, PM2.5 exposure induced severe superficial punctate keratopathy and inflammation in their cornea. In HCETs, cell proliferation and ROS generation followed dose-response and time-dependent manner; meanwhile, mitochondrial ROS (mtROS) level increased and mitochondrial membrane potential (MMP) level decreased. Inflammation cascade was triggered even after short-term exposure. The reduction of ATP production was alleviated with Nrf2 overexpression, NF-κB P65 knockdown, or ROS clearance. Nrf2 overexpression and P65 knockdown reduced inflammatory reaction through decreasing expression of P65 and increasing of Nrf2, respectively. They partly alleviated changes of ROS/mtROS/MMP. This research proved that PM2.5 would cause DED-related inflammation reaction on corneal epithelial cells and further explored its mechanism: ROS from mitochondrial dysfunctions of corneal epithelial cells after PM2.5 exposure partly inhibited the expression of anti-inflammatory protein Nrf2 led the activation of inflammatory protein P65 and its downstream molecules, which finally caused inflammation reaction. Graphical abstract

Inflammatory Cytokines and Chemokines Are Synergistically Induced in a ROS-Dependent Manner by a Co-Culture of Corneal Epithelial Cells and Neutrophil-like Cells in the Presence of Particulate Matter

“…Consistent with previous reports [31], we demonstrated that ROS are involved in cytokine and chemokine production in this co-culture system. PM 2.5 can induce DNA damage in corneal epithelial cells, probably by promoting ROS formation [13].…”

Mechanisms of PM10 Disruption of the Nrf2 Pathway in Cornea

“…In fact, many studies have linked PM exposure to increased visits for several ocular diseases [39][40][41]. Current studies have reported that PM2.5 induces oxidative stress, inflammation [42], apoptosis [43], and autophagy [44] in the cornea. However, the signaling pathways underlying PM10 induced corneal damage are not well understood.…”

“…Current studies have reported that PM 2 . 5 induces oxidative stress, inflammation [42], apoptosis [43], and autophagy [44] in the cornea. However, the signaling pathways underlying PM 10 induced corneal damage are not well understood.…”

Effects of Air Pollution and Meteorological Conditions on DED: Associated Manifestations and Underlying Mechanisms

“…A cell-based and animal exposure study was recently conducted by Chinese researchers, which proved that PM 2.5 would induce DED-related inflammatory response on corneal epithelial cells [17]. This study also explored its etiological mechanism: mitochondria of corneal epithelial cells are dysfunctional after PM 2.5 exposure, then the expression of anti-inflammatory protein Nrf2 was partly inhibited and the inflammatory protein P65 was activated, which eventually triggered an inflammatory reaction [17]. Titanium dioxide (TiO 2 ) nanoparticles, a noncombustible and fine crystalline powder, identified as the PM, were widely used in many commercial products [18].…”

“…Several studies showed that PM exposure upregulated the levels of inflammatory cytokines (IL-1 β , IL-6, IL-8), induced oxidative damage and apoptosis, and decreased cell activity 10 , 12 , 14 , 15 , 16 . A cell-based and animal exposure study was recently conducted by Chinese researchers, which proved that PM 2.5 would induce DED-related inflammatory response on corneal epithelial cells 17 . This study also explored its etiological mechanism: mitochondria of corneal epithelial cells are dysfunctional after PM 2.5 exposure, then the expression of anti-inflammatory protein Nrf2 was partly inhibited and the inflammatory protein P65 was activated, which eventually triggered an inflammatory reaction 17 .…”