PERK and XBP1 differentially regulate CXCL10 and CCL2 production

Area of Science:

• Ophthalmology
• Immunology
• Cell Biology

Background:

• Inflammation is crucial in retinal degenerative diseases.
• Photoreceptor cell involvement in inflammation is poorly understood.
• Endoplasmic reticulum (ER) stress is implicated in cellular dysfunction.

Purpose of the Study:

• To investigate if photoreceptor cells produce inflammatory chemokines CCL2 and CXCL10 during ER stress.
• To elucidate the roles of ER stress pathways (PERK, IRE1α/XBP1) in regulating chemokine production.
• To examine the impact of diabetic complications (AGEs, HG) on this process.

Main Methods:

• Photoreceptor 661W cells treated with ER stress inducers (thapsigargin, AGEs, HG).
• Assessed mRNA and protein levels of CCL2 and CXCL10.
• Utilized gene knockdown (PERK, XBP1) and pathway inhibitors (NF-κB, STAT3).

Main Results:

• ER stress significantly increased CCL2 and CXCL10 expression in photoreceptors.
• PERK pathway activation promoted chemokine expression, while IRE1α/XBP1 suppressed it.
• NF-κB and STAT3 phosphorylation mediated ER stress-induced chemokine production.
• AGEs and HG mimicked ER stress effects, with PERK as a positive and XBP1 as a negative regulator.

Conclusions:

• Photoreceptor cells can contribute to retinal inflammation by producing CCL2 and CXCL10.
• The unfolded protein response pathways PERK and IRE1α/XBP1 differentially regulate ER stress-induced chemokine expression.
• These findings highlight a novel role for photoreceptors in inflammatory responses within the retina.