Biology subjects

Enzmann, V.

Publications and source records attributed to Enzmann, V..

6 recordsLinked to original sources

bioRxiv2025

Comparative analysis of T-cell signatures and astroglial reactivity in Parkinson's pathology across animal models with distinct regenerative capacities

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) and the accumulation of misfolded -synuclein (aSyn). Emerging evidence suggests that the immune system, particularly T-cell-mediated responses, plays a key role in the pathogenesis of PD. However, the heterogeneity of these immune responses across species and preclinical models with varying regenerative capacities remains poorly understood. In this study, we performed a comparative analysis of T-cell infiltration, astroglial reactivity, and DAergic neuronal loss across multiple models and species. These included acute DAergic degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), genetically modified mice with accumulation of aSyn (Thy1-aSyn L61 model), adult zebrafish exposed to MPTP-induced neurotoxicity and human post-mortem midbrain tissue obtained from PD patients. Zebrafish exhibited transient DAergic neurodegeneration followed by neuronal regeneration and a temporary CD4+ T-cell infiltration alongside a regulated astroglial response. In contrast, MPTP-treated mice showed a permanent neuronal loss, increased astrogliosis and CD8+ T-cell infiltration that was negatively correlated with neuronal survival. In contrast, L61 mice exhibited progressive aSyn accumulation with chronic astrogliosis and CD4+ T-cell infiltration not directly linked to neuronal loss. Unlike age-matched controls, the SN from PD brains displayed DAergic degeneration, aSyn aggregation, and elevated CD3+ T-cell infiltration, which correlated with neuronal loss and aSyn burden. These findings emphasise the species- and model-specific immune profiles underlying PD pathology. Our results reveal that CD4+ T-cells contribute to neuronal regeneration following injury in zebrafish. This process is absent in the MPTP and L61 mouse models, which are instead driven by CD8+ or CD4+, respectively. This work underscores the potential of targeted immunomodulation aimed at T cell - glial interactions to slow neurodegeneration and promote repair in PD.

immunology↗

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↗

bioRxiv2022

Oxygen kinetics during CXL using symmetrically and asymmetrically pulsed UV-irradiation

PurposeTo investigate oxygen kinetics during symmetrically pulsed and asymmetrically pulsed crosslinking (p-CXL) with and without supplementary oxygen at different irradiances and corneal depths. DesignExperimental, laboratory study MethodsIn de-epithelialized porcine eyes, a femtosecond-laser generated tunnel was used to place a fibre-probe in corneal depths of 200 and 300 {micro}m to measure the local oxygen concentration. After riboflavin imbibition, the corneas were irradiated at 9, 18 and 30 mW/cm2 for 10 seconds On and 10 seconds Off; while the oxygen concentration was continuously measured until oxygen levels depleted below the oxygen sensors threshold (1%) or until stabilized. All experiments were performed under normoxic (21%) and hyperoxic (>95%) conditions and the obtained data were used to identify parameters of a numerical algorithm for oxygen consumption and diffusion. Following the algorithms development, the suggested asymmetrical pulsing values were experimentally tested. For 9, 18 and 30 mW/cm2 the suggested tested pulsing schemes were 3 seconds On : 9 seconds Off, 2 seconds On : 9 seconds Off and 1 second On : 9 seconds Off respectively. ResultsThe minimum, available stromal oxygen for p-CXL in normoxic environment was decreasing <1% for 9, 18 and 30 mW/cm2 in 200 and 300 m. Using optimized p-CXL, the minimum available oxygen increased to 3.8, 1.8 and 2.8 % at 200 m, for irradiances of 9, 18 and 30 mW/cm2, respectively, where the periods exhibited an equilibrium state. At 300 m, 1.1 % of oxygen was available for 30 mW/cm2. Using a hyperoxic environment, the oxygen concentration was 19.2% using 9 mW/cm2 in 200 m, dropping to 17.0% in 300 m. At 18 mW/cm2, the concentrations were 3.9% and 1% in 200 and 300 m, respectively. Using 30 mW/cm2, all oxygen was depleted below the threshold limit (1% O2) for both depths. Using optimized pulsing in combination with hyperoxic environment, the oxygen concentration was 42.0% using 9 mW/cm2 in 200 m and 43.3% in 300 m. At 18 mW/cm2, the concentrations were 24.7% and 16.1% in 200 and 300 m, respectively. Using 30 mW/cm2, the minimum oxygen availability was 25.7% and 13.7% in 200 and 300 m, respectively. ConclusionSupplementary oxygen during symmetrical and asymmetrical p-CXL increased the oxygen availability during corneal cross-linking. The pulsed irradiance and the hyperoxic environment potentially increased the efficacy of corneal cross-linking in deeper corneal layers and higher irradiances. The numerical algorithm for asymmetrical pulsing led to the quantification of "On" and "Off" times related to different scenarios such as irradiances.

bioengineering↗

bioRxiv2019

Oxidative stress in retinal pigment epithelial cells increased endogenous complement-dependent inflammatory and angiogenic responses - independent from exogenous complement sources

Oxidative stress-induced damage of the retinal pigment epithelium (RPE) together with chronic inflammation has been suggested as major contributors to retinal diseases. Here, we examine the effects of oxidative stress and endogenous complement components on the RPE and its pro-inflammatory and -angiogenic responses.\n\nThe RPE cell line, ARPE-19, treated with H2O2 reduced cell-cell contacts, increased marker for epithelial-mesenchymal transition but showed less cell death. Stressed ARPE-19 cells increased the expression of complement receptors CR3 and C5aR1. CR3 was co-localized with cell-derived complement protein C3, which was observed in its activated form in ARPE-19 cells. C3 as well as its regulators CFH and properdin accumulated in ARPE-19 cells after oxidative stress independent from external complement sources. This cell-associated complement accumulation promoted nlrp3 and foxp3 expression and subsequent increased secretion of pro-inflammatory and pro-angiogenic factors. The complement-associated ARPE-19 reaction to oxidative stress, independent from external complement source, was increased by the PARP-inhibitor olaparib.\n\nOur results indicated that RPE cell-derived complement proteins and receptors are involved in RPE cell homeostasis following oxidative stress and should be considered as targets for treatment developments for retinal degeneration.\n\nO_FIG O_LINKSMALLFIG WIDTH=160 HEIGHT=200 SRC=\"FIGDIR/small/722470v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (79K):\norg.highwire.dtl.DTLVardef@9b5cddorg.highwire.dtl.DTLVardef@1edd562org.highwire.dtl.DTLVardef@15415eborg.highwire.dtl.DTLVardef@16b0a72_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG We show a functional link between oxidative stress, complement receptors, endogenous complement proteins, pro-angiogenic and -inflammatory responses in ARPE-19 cells. These effects are independent from extracellularly added complement proteins or receptor ligands. We suggest an oxidative stress-associated autocrine mechanism of complement receptor regulation in ARPE-19 cells in connection with upregulated intracellular proteases.\n\nHIGHLIGHTSO_LIOxidative stress accumulates complement proteins and receptors in RPE cells\nC_LIO_LIOxidative stress activates the RPE inflammasome without external complement proteins\nC_LIO_LIOxidative stress increases foxp3 expression and IL-8/VEGF secretion in RPE cells\nC_LIO_LIOlaparib enhances pro-inflammatory response of RPE\nC_LI

cell biology↗