Aryl Hydrocarbon Receptor Deficiency Upregulates Intercellular Adhesion Molecule 1 in Retinal Pigment Epithelial Cells and Contributes to Retinal Inflammation

Tsung-Min Yang; Te-Chao Fang; Yu-Cheng Lee; Chen-Chen Lee; Yen-Ju Chan; Ida Fitriana; Yu-Wen Cheng; Ching-Hao Li

doi:10.1016/j.labinv.2025.104197

Aryl Hydrocarbon Receptor Deficiency Upregulates Intercellular Adhesion Molecule 1 in Retinal Pigment Epithelial Cells and Contributes to Retinal Inflammation

Lab Invest. 2025 May 21;105(9):104197. doi: 10.1016/j.labinv.2025.104197. Online ahead of print.

Authors

Tsung-Min Yang¹, Te-Chao Fang², Yu-Cheng Lee³, Chen-Chen Lee⁴, Yen-Ju Chan¹, Ida Fitriana⁵, Yu-Wen Cheng⁶, Ching-Hao Li⁷

Affiliations

¹ Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
² Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Taipei Medical University Research Center of Urology and Kidney (RCUK), School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
³ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁴ Department of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, Taiwan.
⁵ Department of Pharmacology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia.
⁶ School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Taipei Medical University Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan. Electronic address: ywcheng@tmu.edu.tw.
⁷ Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Taipei Medical University Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan. Electronic address: bros22@tmu.edu.tw.

PMID: 40409542
DOI: 10.1016/j.labinv.2025.104197

Abstract

Retinal pigment epithelium (RPE) cells, located between the photoreceptors and choroid, play a crucial role in maintaining retinal health and function. They act as immunosuppressive barriers, preventing immune cell infiltration from the choroid. Retinal inflammation contributes to the development of various ocular diseases. The aryl hydrocarbon receptor (AHR) is a well-established ligand-dependent transcription factor that mediates potent anti-inflammatory signals following ligand binding. AHR expression is notably reduced under several conditions that negatively affect the retina. We hypothesized that AHR protein loss may impair RPE cell function, shifting them toward a proinflammatory phenotype. In this study, we investigated the proinflammatory pathways activated by AHR knockout (AHR-KO) and examined associated retinal phenotypic changes in AHR-KO mice. Our findings suggest that AHR deficiency may enhance the activity of αvβ3-integrin, extracellular signal-regulated kinase 1/2, and p65 subunit of nuclear factor kappa B, leading to an upregulation of intercellular adhesion molecule 1 (ICAM1) and promoting monocyte adhesion in vitro. Introducing an AHR-green fluorescent protein into AHR-KO RPE cells or pretreating the cells with pharmacologic inhibitors targeting αvβ3 (cyclo[RGDfk]), focal adhesion kinase (PF573228), phospholipase C (U73122), extracellular signal-regulated kinase 1/2 (U0126), and nuclear factor kappa B (Bay11-7082) prevented ICAM1 induction in AHR-KO RPE cells. These results suggest that the proinflammatory pathway is driven by AHR deficiency. In AHR-KO mice, retinal tissues showed ICAM1 accumulation, microglial activation, and migration, indicating chronic retinal inflammation because of AHR deficiency. These mice also displayed early-onset electroretinogram degeneration. Collectively, our data support the protective role of AHR in maintaining RPE cell physiology and retinal health.

Keywords: aryl hydrocarbon receptor; intercellular adhesion molecule 1; retinal inflammation; retinal pigment epithelium; αvβ3-integrin.