Hypoxic Processes Induce Complement Activation via Classical Pathway in Porcine Neuroretinas

Abstract

Considering the fact that many retinal diseases are yet to be cured, the pathomechanisms of these multifactorial diseases need to be investigated in more detail. Among others, oxidative stress and hypoxia are pathomechanisms that take place in retinal diseases, such as glaucoma, age-related macular degeneration, or diabetic retinopathy. In consideration of these diseases, it is also evidenced that the immune system, including the complement system and its activation, plays an important role. Suitable models to investigate neuroretinal diseases are organ cultures of porcine retina. Based on an established model, the role of the complement system was studied after the induction of oxidative stress or hypoxia. Both stressors led to a loss of retinal ganglion cells (RGCs) accompanied by apoptosis. Hypoxia activated the complement system as noted by higher C3+ and MAC+ cell numbers. In this model, activation of the complement cascade occurred via the classical pathway and the number of C1q+ microglia was increased. In oxidative stressed retinas, the complement system had no consideration, but strong inflammation took place, with elevated TNF, IL6, and IL8 mRNA expression levels. Together, this study shows that hypoxia and oxidative stress induce different mechanisms in the porcine retina inducing either the immune response or an inflammation. Our findings support the thesis that the immune system is involved in the development of retinal diseases. Furthermore, this study is evidence that both approaches seem suitable models to investigate undergoing pathomechanisms of several neuroretinal diseases.

In a novel autoimmune and high-pressure glaucoma model a complex immune response is induced

“…Now, co-staining of complement markers with Iba1 showed that C1q was often co-localized with Iba1 + microglia/macrophages, while only few C3 + or MAC + cells showed co-localization with Iba1. Similar results were noted in a porcine organ culture model, where damage was induced by oxidative stress or hypoxia (58). It is well known that microglia can express complement proteins, including C1q (56, 59, 60).…”

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

“…Hypoxia induces adaptive response to maintain the homeostasis of intracellular environment and promote cell survival (Kong et al 2022 ; Qureshi-Baig et al 2020 ). For others, hypoxia induces cell death by activating apoptosis (Ren et al 2021 ; Mueller-Buehl et al 2021 ). The research on the changes of metabolic function caused by hypoxia and its mechanism will help to understand the pathogenesis of hypoxic diseases.…”

Protection against Oxidative Stress by Coenzyme Q10 in a Porcine Retinal Degeneration Model

“…The lack of changes in the microglial mRNA expression could be due to the CoQ10 concentrations used, the time points, or a difference between cell presence and gene expression. Discrepancies between expression and cellular occurrence were already seen in other studies and might be related to post-transcriptional and translational regulations [31,56,57].…”

“…Three sections per explant were stained with hematoxylin + eosin (HE) [31]. The thickness of the retina was measured in three different areas of two photos per section via ZEN 2012 imaging software (Carl Zeiss MicroImaging GmbH, Oberkochen, Germany).…”