Project: X06

This crosslinking project investigates the role of Interleukin-6 (IL-6) signaling and obesity-associated IL-6 resistance in retinal neuroinflammation and glaucoma progression. Glaucoma is one of the leading causes of irreversible blindness worldwide and is characterized by progressive degeneration of retinal ganglion cells (RGCs). While elevated intraocular pressure (IOP) is a major risk factor, increasing evidence suggests that inflammatory signaling pathways, particularly IL-6-mediated neuroinflammation, substantially contribute to retinal damage and neurodegeneration.

Clinical observations and preliminary experimental data indicate that obesity-associated chronic low-grade inflammation may induce a state of IL-6 resistance that alters inflammatory responses in peripheral tissues and potentially also within the retina. Interestingly, although obesity is associated with elevated IOP, several studies suggest that the overall risk of developing glaucoma may not increase proportionally. Preliminary findings from this consortium further demonstrate reduced retinal ganglion cell loss and attenuated neuroinflammation in obese, IL-6-resistant experimental models, suggesting the existence of endogenous neuroprotective mechanisms.

This project combines expertise from projects C01, C02, C04, and C08 to investigate how IL-6 resistance influences retinal immune homeostasis and susceptibility to glaucomatous neurodegeneration. Using diet-induced obesity models, genetically modified mice, and experimental glaucoma paradigms, the project will characterize IL-6-responsive retinal cell populations, inflammatory signaling pathways, microglial activation, and retinal ganglion cell survival under conditions of elevated IOP. Particular emphasis will be placed on identifying cell type-specific IL-6 receptor signaling mechanisms and downstream neuroprotective pathways.

To bridge experimental findings with translational relevance, IL-6 levels and signaling patterns will additionally be analyzed in aqueous humour samples from glaucoma patients and non-glaucomatous controls. These analyses will be integrated with clinical parameters such as body mass index (BMI), glaucoma prevalence, and intraocular pressure data, as well as publicly available and newly generated single-cell transcriptomic datasets from human glaucoma studies.

By linking neuroinflammation, metabolic regulation, and retinal degeneration, this project establishes a novel interdisciplinary framework within SFB 1607 for understanding endogenous neuroprotective immune mechanisms in glaucoma. The findings are expected to uncover new mechanistic insights into IL-6 signaling, identify potential biomarkers of retinal immune regulation, and support the development of innovative neuroprotective therapeutic strategies for glaucoma and related retinal diseases.

Key Methods