Biology subjects

Conedera, F. M.

Publications and source records attributed to Conedera, F. M..

3 recordsLinked to original sources

bioRxiv2024

Glia-Mediated Antigen Presentation In The Retina During Degeneration

Glia antigen-presenting cells (APCs) are pivotal regulators of immune surveillance within the retina, maintaining tissue homeostasis and promptly responding to insults. The intricate mechanisms underlying their local coordination and activation remain unclear. Our study integrates an animal model of retinal injury, retrospective analysis of human retinas, and in vitro experiments to elucidate insights into the pivotal role of antigen presentation in neuroimmunology during retinal degeneration, uncovering the involvement of various glial cells, notably Muller glia, and microglia. Glial cells act as sentinels, detecting antigens released during degeneration and interacting with T-cells via MHC molecules, which are essential for immune responses. Microglia function as APCs via the MHC class II pathway, upregulating key molecules such as Csf1r and cytokines. In contrast, Muller cells act as atypical APCs through the MHC class I pathway, exhibiting upregulated antigen processing genes and promoting a CD8+ T-cell response. Distinct cytokine signaling pathways, including TNF- and IFN, contribute to the immune balance. Human retinal specimens corroborate these findings, demonstrating glial activation and MHC expression correlating with degenerative changes. In vitro assays also confirmed differential T-cell migration responses to activated microglia and Muller cells, highlighting their role in shaping the immune milieu within the retina. These insights emphasize the complex interplay between glial cells and T-cells, influencing the inflammatory environment and potentially modulating degenerative processes. In summary, our study emphasizes the involvement of retinal glial cells in modulating the immune response after insults to the retinal parenchyma. Thus, unraveling the intricacies of glia-mediated antigen presentation in retinal degeneration is essential for developing precise therapeutic interventions for retinal pathologies.

neuroscience↗

bioRxiv2023

Modulation of Extracellular Matrix Composition and Chronic Inflammation by Pirfenidone Promotes Scar Reduction in Retinal Wound Repair

Wound repair in the retina is a complex mechanism and a deeper understanding of it is necessary for the development of effective treatments to slow down or even prevent degenerative processes leading to photoreceptor loss. In this study, we harnessed a laser-induced retinal degeneration model, enabling a profound molecular elucidation and a comprehensive, prolonged observation of the wound healing sequence in a murine laser-induced degeneration model until day 49 post laser. Our observations included the expression of specific extracellular matrix proteins and myofibroblast activity, along with an analysis of gene expression related to extracellular matrix and adhesion molecules through RNA measurements. Furthermore, the administration of pirfenidone, an anti-inflammatory and anti-fibrotic compound, was used to modulate the scar formation after laser treatment. Our data revealed upregulated collagen expression in late regenerative phases and sustained inflammation in the damaged tissue. Notably, treatment with pirfenidone was found to mitigate scar tissue formation, effectively downregulating collagen production and diminishing the presence of inflammatory markers. However, it did not lead to the regeneration of the photoreceptor layer.

neuroscience↗

bioRxiv2023

MACROPHAGES COORDINATE IMMUNE RESPONSE TO LASER-INDUCED INJURY VIA EXTRACELLULAR TRAPS

Macrophages/monocytes, the primary contributors to chronic inflammation in degenerated retinas, orchestrate intricate immune responses. They remain enigmatic in their local coordination and activation mechanisms. Innovations in experimental systems enable real-time exploration of immune cell interactions and temporal dimensions in response. In preclinical mouse models, we use in vivo microscopy to unravel how macrophages/monocytes govern microglia and PL responses spatio-temporally. Our findings underscore the pivotal role of innate immune cells, especially macrophages/monocytes, in regulating retinal repair. The absence of neutrophil and macrophage infiltration aids parenchymal integrity restoration, while their depletion, particularly macrophages/monocytes, impedes vascular recovery. Innate immune cells, when activated, release chromatin and granular proteins, forming extracellular traps (ETs), critical for tissue repair by modulating neutrophil and T-cell responses. Our investigations demonstrate that pharmacological inhibition of ETosis with Cl-amidine enhances retinal and vascular repair, surpassing the effects of blocking innate immune cell recruitment. Simultaneously, Cl-amidine treatment reshapes the inflammatory response, causing neutrophils, helper, and cytotoxic T-cells to cluster primarily in the superficial capillary plexus, affecting retinal microvasculature perfusion. Our data offer novel insights into innate immunitys role in responding to retinal damage, potentially informing more effective immunotherapeutic strategies for neurodegenerative diseases.

neuroscience↗