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Published on: March 23, 2016
Macrophage Migration Inhibitory Factor (MIF)-CD74 Signaling Pathway Mediates Trabecular Meshwork Dysfunction in
Monu Monu1, Lal Krishan Kumar1, Prince Kumar1
1Department of Ophthalmology, Mason Eye Institute, University of Missouri School of Medicine, Columbia, Missouri, USA.
Purpose:
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in many inflammatory and fibrotic diseases; however, its role in primary open-angle glaucoma (POAG) and trabecular meshwork (TM) dysfunction remains unknown. In this study, we investigated whether MIF-CD74 signaling regulates TM pathobiology through modulation of the transcription factor, Blimp-1, and downstream cytoskeletal reorganization and extracellular matrix (ECM) remodeling.
Method:
Primary human TM cells (HTMC) were exposed to glaucomatous stressors, including TGF-β2, rMIF, or a pro-inflammatory milieu. Expression of MIF, its receptor CD74, and Blimp-1 was measured by qPCR and immunoblotting. ECM proteins and phosphorylated myosin-light chain (pMLC) were evaluated by immunofluorescence staining. In vivo, MIF-CD74 and Blimp-1 expression were examined in the TM/anterior segment (AS) tissue of Tg.CreMYOCY437H and lentiviral (LV)-TGF-β2-induced ocular hypertension (OHT) mouse models. Functional involvement of MIF signaling in TM pathobiology was examined using the irreversible MIF inhibitor 4-IPP and the immunomodulatory metabolites agmatine and thiamine.
Results:
Glaucomatous stressors significantly upregulated MIF and CD74 expression with concomitant suppression of Blimp-1 in HTMC. Similarly, TM/AS tissue from both OHT models (Tg.CreMYOCY437H and LV-TGF-β2) demonstrated increased MIF-CD74 expression accompanied by reduced Blimp-1 levels. Activation of MIF-CD74 signaling triggered pro-inflammatory and cell death pathways and promoted ECM remodeling, characterized by increased fibrotic protein expression and enhanced RhoA/ROCK-mediated MLC phosphorylation, indicating modulation of TM contractility. Pharmacological inhibition of MIF attenuated inflammatory signaling, reduced ECM deposition and cytoskeletal remodeling, and suppressed RhoA/ROCK/MLC activation, restoring a protective TM phenotype.
Conclusion:
Our findings identify MIF-CD74 signaling as a previously unrecognized regulator of TM dysfunction in POAG. MIF-mediated suppression of Blimp-1 mechanistically links inflammatory signaling to cytoskeletal contractility and fibrotic ECM remodeling, key determinants of aqueous humor outflow resistance. Targeting the MIF-CD74/Blimp-1 axis may represent a novel therapeutic strategy to restore TM homeostasis and reduce intraocular pressure in glaucoma.
Insights
Macrophage migration inhibitory factor (MIF) signaling drives trabecular meshwork dysfunction in primary open-angle glaucoma by suppressing Blimp-1. Inhibiting MIF restores TM function and may offer new glaucoma treatments.
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.
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