Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy

Abstract

Retinal neurodegenerative diseases involve a scenario of inflammation and cell death that leads to morphological alterations and visual impairment. Non-ocular inflammatory processes could affect neurodegenerative retinal disorders and their progression, at least in part by activating microglial cells and releasing pro-inflammatory cytokines. Our purpose was to study the consequences of a systemic inflammatory process in the progression of retinal degeneration in P23H rats, a retinitis pigmentosa (RP) model. In order to induce a mild chronic systemic inflammation, we administered low doses of lipopolysaccharide (LPS) from age P20 to P60 to dystrophic P23H rats and healthy SD rats. Visual responsiveness was assessed by electroretinography (ERG). The morphological state of the retinas was analyzed by fluorescent immunohistochemistry (IHC), evaluating the number, morphology, and connectivity of different neuronal populations by means of cell type-specific markers. Microglia density, distribution, and degree of activation were evaluated by IHC and flow cytometry. The expression levels of inflammation- and apoptosis-related genes were analyzed by qRT-PCR arrays. Low-dose LPS administration did not induce significant functional or morphological changes in the retina of SD rats, although at the molecular level, we detected expression changes in genes related to apoptosis. Otherwise, systemic injection of LPS into P23H rats induced a further deterioration in the ERG response, with greater loss of photoreceptors and worsening of synaptic connectivity, accompanied by increasing numbers of microglial cells, which also showed a more intense activation state. Several inflammation- and apoptosis-related genes were upregulated. Our results indicate that chronic exacerbation of the inflammatory response in response to LPS accelerates neurodegeneration in dystrophic P23H rats, suggesting that in patients with ocular neurodegenerative diseases, peripheral damage, as a systemic infection or chronic inflammatory process, could accelerate disease progression, and should be taken into account in order to select an appropriate therapy to revert, block or slow-down the degenerative process.

Gradual Increase in Environmental Light Intensity Induces Oxidative Stress and Inflammation and Accelerates Retinal Neurodegeneration

“…5,10,[57][58][59][60][61][62] In all retinal degenerative diseases, photoreceptor degeneration is accompanied by the proliferation and activation of resident microglia and by the recruitment of immune cells as monocytes and macrophages, which contribute to the inflammatory state of the tissue. 10,31,33 Accordingly, our results show an increase in the immune cells implicated in the inflammatory process in rd10 mice. However, rd10 mice raised in different light conditions showed few differences in the immune-related cells populations, probably due to the advanced state of the degenerative process at the endpoint of the study (P30).…”

“…Cornea, lens, and vitreous body were removed, and the eyecups were prepared for cross-sectional cryosections as previously described by our group. [30][31][32] Sections 16-μm thick were obtained and stored at -20°C.…”

Retinal Vascular Degeneration in the Transgenic P23H Rat Model of Retinitis Pigmentosa

“…The gradual photoreceptor loss characteristic of P23H line-3 rats provides an experimental model closer to RP patients than other animal models (Machida et al, 2000 ; Cuenca et al, 2004 ). This vascular study completes a series of studies conducted by our research group analyzing the morphological and functional changes occurring during the degenerative process of homozygous P23H line-3 rats, including changes in astrocytes, microglia and Müller cells (Esquiva et al, 2017 ; Cuenca et al, 2014 ; Fernández-Sánchez et al, 2015a ; Lax et al, 2016 ; Noailles et al, 2016 , 2018 ). We have chosen homozygous vs. heterozygous P23H line-3 rats because our previous results have demonstrated that degeneration in the homozygous model is more aggressive but slow enough to properly assess neuroprotective effects of various compounds (Fernández-Sánchez et al, 2011 , 2012a , b , 2015b , 2017 ; Lax et al, 2011 ; Noailles et al, 2014 ).…”

Sectoral activation of glia in an inducible mouse model of autosomal dominant retinitis pigmentosa

“…www.nature.com/scientificreports/ their microglia display smaller round bodies with few dendrites 30,31 . In the more slowly progressive P23H RHO rat and P23H Rho mouse, microglia retract their dendrites yet maintain an intermediate ramified phenotype 27,32,33 . Thus morphological activation of microglia towards a large, ameboid phenotype likely occurs in proportion to the size of the phagocytic bolus introduced by retinal degeneration, and may have important implications for cell signaling, such as the production of IL-1β 34 .…”