[Literature Interpretation] CD40–CD154 Interaction Induces Progressive Neurodegeneration in Mice with Acute Ocular Hypertension
Release time:
2026-10-09
1. Background
Glaucoma, as a neurodegenerative disease, mainly causes the loss of retinal ganglion cells (RGCs) and optic nerve axons, leading to visual field defects and irreversible blindness. Elevated intraocular pressure (IOP) is the most important pathogenic factor for glaucoma. However, clinically used IOP-lowering treatments cannot completely prevent continued visual field damage in some glaucoma patients. This suggests that mechanisms of glaucoma pathogenesis beyond elevated IOP still need to be explored. This study aimed to investigate the role and mechanism of the CD40–CD154 interaction in acute ocular hypertension-induced progressive retinal inflammation and injury.
Elucidating the function of the CD40–CD154 interaction may further reveal the mechanism by which retinal neurodegeneration continues to progress after IOP returns to normal, and may provide a theoretical basis for the future identification of effective therapeutic targets for glaucoma.
CD154 (also known as CD40L) is a transmembrane protein expressed by activated T cells. Studies have confirmed that in hypertensive glaucoma, CD154 can accelerate the senescence and apoptosis of retinal ganglion cells (RGCs) co-cultured with Müller cells.
CD40 is mainly expressed on the surface of antigen-presenting cells. In an ischemia/reperfusion-induced retinopathy model, CD40 knockout (CD40−/−) mice showed significantly reduced inflammatory responses, ganglion cell loss, and capillary degeneration in the ischemic retina.
The CD40–CD154 interaction is not only a costimulatory signal for T cell activation but also a key factor regulating antigen-presenting cell activation. Previous studies have shown that T cell-derived CD154 can initiate atherosclerosis by activating interferon-γ (IFN-γ), thereby inducing immune cell recruitment, necrotic core formation, and fibrous cap thinning.
2. Methods
Transmission electron microscopy was used to observe optic nerve morphology at different time points in the acute ocular hypertension model group and sham group of C57BL/6 mice; Western blotting was used to detect the relative expression levels of CD40 and CD154 at different time points.
CD40 small interfering RNA and CD154 small interfering RNA were used to knock down CD40 and CD154 expression, respectively, and glaucoma-related neural damage was evaluated by optic nerve axon counting and transmission electron microscopy imaging.
Immunofluorescence was used to detect the localization of CD154 and CD40 in mouse retinas; flow cytometry was used to detect the expression of CD154 and CD40 in mouse spleens and the distribution of CD4⁺ T cell subsets.
Acute ocular hypertension (IOP) modeling was performed in 6–8-week-old mice: a 30G needle was connected to a sterile saline bag through a disposable infusion tube, and the saline bag was elevated to approximately 100 cm to complete assembly of the modeling apparatus.
Mice were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (50 mg/kg) and received topical ocular anesthesia with proparacaine hydrochloride eye drops; after pupil dilation with compound tropicamide, a 30G needle was inserted into the peripheral cornea approximately 1 mm from the corneoscleral limbus, avoiding injury to the iris and lens and preventing the needle from passing through the cornea. After the needle was secured, the infusion switch was turned on to maintain elevated IOP for 1 hour. The sham group underwent anterior chamber paracentesis only, without IOP elevation. After needle removal, levofloxacin ophthalmic gel was applied to the ocular surface to prevent infection.
A rebound tonometer Tonolab for mice and rats (Icare Finland Oy, Helsinki, Finland) was used to measure and record IOP before, during, and after acute ocular hypertension modeling. In addition, retinas and spleens were harvested on days 1, 3, 7, and 14 after modeling for subsequent experiments.
3. Results
After IOP returned to normal in the modeled mice, axon loss continued. Both CD40 and CD154 expression were increased in glaucomatous mice. Compared with the 7-day modeling group, the number of axons was significantly increased after CD40 or CD154 knockdown. CD40 and CD154 were co-localized in the retina. The distribution trend of T cell subsets in the spleen, especially Th1 cells, was consistent with the expression trends of CD40 and CD4⁺CD154⁺.
4. Conclusions
The CD40–CD154 interaction participates in progressive neurodegeneration in glaucoma after IOP returns to normal. T helper 1 (Th1) cells play a critical role in neural damage in glaucomatous mice.
5. Publication Information
Authors: Jiahan Tang; Zhe Feng; Nan Jiang; Guiqiu Zhao
Journal: Investigative Ophthalmology & Visual Science
October 2025, Vol. 66, 39.
doi: https://doi.org/10.1167/iovs.66.13.39
Original article link: https://iovs.arvojournals.org/article.aspx?articleid=2811000&resultClick=1
Previous
Related News
