**Background:** Particulate matter (PM) is a major air pollutant linked to various health issues, including ocular diseases. The retina, particularly the retinal pigment epithelium (RPE), is vulnerable to PM-induced damage, which may involve inflammation and endoplasmic reticulum (ER) stress. This study aimed to investigate whether PM exposure induces inflammation and ER stress in human RPE cells (ARPE-19) and to elucidate the underlying molecular mechanisms.
**Methods:** ARPE-19 cells were treated with PM (PM10-like; European reference material ERM-CZ120) at concentrations ranging from 0 to 2000 μg/mL. Inflammatory responses were assessed by measuring phosphorylation of MAPK (p38, JNK, ERK) and NFκB pathway proteins via western blot, and mRNA expression of cytokines (TNFα, IL-1β, IL-6, MCP-1) via qRT-PCR. The role of ERK was tested using the MEK inhibitor U0126 (20 μM). ER stress was evaluated by qRT-PCR for BiP, CHOP, and XBP-1 mRNA, and western blot for UPR proteins (PERK, eIF2α, ATF4, CHOP, IRE1α, XBP-1, BiP). Intracellular calcium ([Ca²⁺]i) was measured using Fluo-4 NW assay. Hypoxia markers (VEGFα, ANKRD37) and tight junction integrity (ZO-1) were also analyzed. Cell viability was assessed by MTT assay.
**Key Results:** PM did not significantly affect cell viability at any concentration (0-2000 μg/mL) for 2 h. However, with 0.01% Tween-80, 2 mg/mL PM reduced viability to 87% at 4 h and 83% at 8 h. PM dose-dependently increased phosphorylation of p38, JNK, ERK, IκBα, and NFκB at concentrations ≥100 μg/mL (p<0.05). U0126 pretreatment significantly inhibited PM-induced phosphorylation of p38, ERK, IκBα, and NFκB. PM significantly upregulated mRNA expression of TNFα (≥250 μg/mL), IL-1β (≥50 μg/mL), IL-6 (≥250 μg/mL), and MCP-1 (≥50 μg/mL). U0126 also attenuated these cytokine mRNA increases. PM (2 mg/mL with Tween-80) increased ER stress markers: BiP mRNA peaked at 4 h, CHOP at 2 h, and XBP-1 at ≥2 h. Western blot showed increased protein levels of PERK, eIF2α, ATF4, CHOP, IRE1α, XBP-1, and BiP. [Ca²⁺]i levels increased dose-dependently up to 250 μg/mL PM, then decreased at higher doses. Hypoxia markers VEGFα and ANKRD37 were significantly elevated, while ZO-1 mRNA decreased time-dependently.
**Clinical Implications:** This study provides mechanistic evidence that PM exposure can directly induce inflammation and ER stress in retinal pigment epithelial cells, potentially contributing to the pathogenesis of retinal diseases such as age-related macular degeneration and diabetic retinopathy. The activation of MAPK/NFκB and UPR pathways suggests that these could be therapeutic targets to mitigate PM-induced ocular damage. The findings underscore the importance of reducing air pollution exposure to protect ocular health, especially in vulnerable populations.