UC Berkeley

Glaucoma is a chronic neurodegenerative disease characterized by progressive retinal ganglion cell loss and irreversible vision decline. Although elevated intraocular pressure is a major risk factor, pressure-lowering therapies do not fully prevent disease progression, indicating that additional mechanisms contribute to retinal injury. Among these, Müller glia are increasingly recognized as central regulators of retinal homeostasis whose responses to mechanical, metabolic, and inflammatory stress can determine whether the retina adapts to injury or progresses toward chronic dysfunction. This dissertation investigates Müller glia as both mediators and therapeutic targets in glaucomatous neuroinflammation, with particular emphasis on the endogenous neuroprotective lipid mediator Lipoxin B4 (LXB4). Chapter 1 provides the biological framework for the dissertation by reviewing Müller glia in health and disease. It highlights their essential roles in structural support, neurotransmitter recycling, ion and water homeostasis, and neurovascular regulation, and examines how these functions become disrupted under sustained stress. Particular emphasis is placed on glaucoma as a disease in which biomechanical strain, inflammatory signaling, and neuronal vulnerability converge to drive maladaptive glial reactivity. Chapter 2 examines lipid mediator signaling in the eye and positions lipoxins, particularly LXB4, as endogenous regulators of inflammatory control and tissue protection. This chapter synthesizes evidence that protective lipid pathways operate across ocular tissues and that LXB4 is an emerging neuroprotective mediator in the retina. Prior studies identifying lipoxin signaling in retinal astrocytes, microglia, and retinal ganglion cells support a multicellular model of retinal protection, while also revealing a key unresolved question: whether Müller glia directly participate in LXB4 biosynthesis and signaling. Chapter 3 addresses this question experimentally and identifies Müller glia as both a source and target of LXB4 signaling during ocular hypertension. Using primary Müller glia, immortalized Müller glia, lipidomics, transcriptomic analyses, and mouse models of ocular hypertension, this work demonstrates that Müller glia express a functional lipoxin biosynthetic pathway and endogenously generate LXB4. Ocular hypertension induced Müller glia reactivity, increased TRPV4 expression, and activated inflammatory pathways including IL-6/STAT3 signaling. Pharmacologic activation of TRPV4 recapitulated these reactive changes in vitro, whereas LXB4 suppressed TRPV4-associated gliosis, reduced inflammatory gene expression, decreased STAT3 phosphorylation, and limited TRPV4 upregulation in vivo. These findings identify a previously unrecognized Müller glia–LXB4 regulatory circuit linking mechanosensitive stress signaling to endogenous retinal protection. Chapter 4 extends this framework to Müller glia structure by developing an FFT-based workflow to quantify directional organization of RLBP1-labeled Müller glia stalks in retinal sections. This approach demonstrates that ocular hypertension disrupts Müller glia-associated structural organization, particularly in ganglion cell layer-associated regions, and that LXB4 partially preserves this organization in acute ocular hypertension. These findings establish structural remodeling as a quantifiable readout of glia state and provide a practical method for measuring Müller glial-associated tissue disorganization in disease. Taken together, this dissertation identifies LXB4 as a central protective pathway in glaucomatous retinal stress and establishes Müller glia as both contributors to disease progression and targets for therapeutic modulation. More broadly, these studies support a model in which effective neuroprotection in glaucoma may require not only control of intraocular pressure, but also restoration of endogenous lipid-mediated pathways that limit chronic gliosis and preserve retinal homeostasis.