{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:07:05Z","timestamp":1774372025989,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,20]]},"group-title":"Immunology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Health (NIH)\/ National Eye Institutes","award":["R01EY032495"],"award-info":[{"award-number":["R01EY032495"]}]},{"name":"National Institute of Health (NIH)\/ National Eye Institutes","award":["R01EY026177"],"award-info":[{"award-number":["R01EY026177"]}]},{"name":"University of Missouri School of Medicine, Columbia, MO","award":["Research start-up funds"],"award-info":[{"award-number":["Research start-up funds"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Method<\/jats:title>\n                  <jats:p>\n                    Primary human TM cells (HTMC) were exposed to glaucomatous stressors, including TGF-\u03b22, 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.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , MIF-CD74 and Blimp-1 expression were examined in the TM\/anterior segment (AS) tissue of Tg.CreMYOC\n                    <jats:sup>Y437H<\/jats:sup>\n                    and lentiviral (LV)-TGF-\u03b22-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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    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.CreMYOC\n                    <jats:sup>Y437H<\/jats:sup>\n                    and LV-TGF-\u03b22) 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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.18.712673","type":"posted-content","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T06:30:10Z","timestamp":1774074610000},"source":"Crossref","is-referenced-by-count":0,"title":["Macrophage Migration Inhibitory Factor (MIF)-CD74 Signaling Pathway Mediates Trabecular Meshwork Dysfunction in Glaucoma"],"prefix":"10.64898","author":[{"given":"Monu","family":"Monu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Mason Eye Institute, University of Missouri School of Medicine, Columbia, Missouri, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lal Krishan","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Mason Eye Institute, University of Missouri School of Medicine, Columbia, 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