Macrophage Migration Inhibitory Factor (MIF)-CD74 Signaling Pathway Mediates Trabecular Meshwork Dysfunction in...

Area of Science:

• Ophthalmology
• Immunology
• Cell Biology

Background:

• Macrophage migration inhibitory factor (MIF) is a cytokine involved in inflammatory and fibrotic diseases.
• The role of MIF in primary open-angle glaucoma (POAG) and trabecular meshwork (TM) dysfunction is currently unknown.
• Understanding MIF's role in TM pathology is crucial for developing new glaucoma therapies.

Purpose of the Study:

• To investigate the role of MIF-CD74 signaling in TM pathobiology.
• To determine if MIF-CD74 signaling modulates the transcription factor Blimp-1.
• To examine the downstream effects on cytoskeletal reorganization and extracellular matrix (ECM) remodeling in TM cells.

Main Methods:

• Primary human TM cells (HTMC) were treated with glaucomatous stressors (TGF-β2, rMIF, pro-inflammatory milieu).
• MIF, CD74, and Blimp-1 expression were quantified using qPCR and immunoblotting.
• ECM proteins, pMLC, and MIF-CD74/Blimp-1 expression were assessed in mouse models of ocular hypertension (OHT).
• Functional effects were evaluated using MIF inhibitors and immunomodulatory metabolites.

Main Results:

• Glaucomatous stressors increased MIF and CD74 expression while decreasing Blimp-1 in HTMC and OHT mouse models.
• MIF-CD74 activation promoted inflammation, cell death, and ECM remodeling, including increased fibrotic proteins and RhoA/ROCK-mediated pMLC.
• MIF inhibition reduced inflammatory signaling, ECM deposition, and cytoskeletal remodeling, restoring a protective TM phenotype.

Conclusions:

• MIF-CD74 signaling is a novel regulator of TM dysfunction in POAG.
• MIF suppresses Blimp-1, linking inflammation to TM contractility and ECM remodeling, thereby increasing outflow resistance.
• Targeting the MIF-CD74/Blimp-1 axis presents a potential therapeutic strategy for glaucoma to restore TM homeostasis and reduce intraocular pressure.