Immunosuppression, peripheral inflammation and invasive infection from endogenous gut microbiota activate retinal microglia in mouse models

Maneu, Victoria; Noailles, Agustina; Gómez‐Vicente, Violeta; Carpena, Núria; Cuenca, Nicolás; Gil, M. Luisa; Gozalbo, Daniel

doi:10.1111/1348-0421.12405

Cited by 11 publications

(8 citation statements)

References 42 publications

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“…The LPS-induced microglial activation observed in P23H rat retinas is in agreement with our previous works and those by others, showing that systemic infections caused by cytomegalovirus 15 or Candida albicans 16 , as well as peripheral insults 17 are capable of triggering microglial activation and increasing the quantity of microglial cells in the retina. The higher number of Iba1-positive cells in the retina of LPS-injected P23H rats could be caused by migration of inflammatory macrophages, myeloid precursors, or inflammatory monocytes, or by the proliferation of retinal microglia, as these cell types are able to proliferate in situ once they have differentiated 36 .…”

Section: Discussionsupporting

confidence: 93%

“…Also, retinal neurodegenerative diseases, such as retinitis pigmentosa (RP) 3 , age-related macular degeneration 12 , and glaucoma 13 , 14 are concomitant with chronic microglial activation and neuroinflammatory process. Retinal microglial cells may also be activated by systemic infection by fungus or virus 15 , 16 and by immunosuppression or peripheral inflammation 17 , which could worsen the degenerative process. However, the mechanisms by which systemic inflammation and microglial activation exert their effects on chronic neurodegeneration are not yet widely understood.…”

Section: Introductionmentioning

confidence: 99%

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Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy

et al. 2018

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“…Different neurotransmitters are also known to activate microglia via their respective receptors, such as purinergic receptors, glutamate receptors, dopaminergic receptors and cholinergic receptors [9]. The immune cells and molecules (e.g., complement, inflammasome associated protein, gut microbiota, and the bacterial secreted metabolisms [19,20,21]) known to induce peripheral inflammation can also induce microglial activation.…”

Section: Microglia Are the Central Modulators Of Neuroinflammationmentioning

confidence: 99%

Physical Exercise Inhibits Inflammation and Microglial Activation

Mee-inta

Zhao

Kuo

2019

Cells

181

126

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Accumulating evidence indicates that exercise can enhance brain function and attenuate neurodegeneration. Besides improving neuroplasticity by altering the synaptic structure and function in various brain regions, exercise also modulates multiple systems that are known to regulate neuroinflammation and glial activation. Activated microglia and several pro-inflammatory cytokines play active roles in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. The purpose of this review is to highlight the impacts of exercise on microglial activation. Possible mechanisms involved in exercise-modulated microglial activation are also discussed. Undoubtedly, more studies are needed in order to disclose the detailed mechanisms, but this approach offers therapeutic potential for improving the brain health of millions of aging people where pharmacological intervention has failed.

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“…In this context, a few recent studies have linked gut microbiome changes with some retinal degenerative diseases [33,34], including age-related macular degeneration (AMD) [35][36][37][38][39], glaucoma [40][41][42][43] and diabetic retinopathy [44], even though the published results vary depending on the type and stage of the disease and between studies. On the other hand, in a previous study we have demonstrated that invasive infection from gastrointestinal microbiome can induce activation of retinal microglia [45], the primary resident immune cell of the retina.…”

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confidence: 84%

Retinitis Pigmentosa Is Associated With Shifts in The Gut Microbiome

Kutsyr

Maestre‐Carballa

Lluesma-Gomez

et al. 2020

Preprint

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Background: The gut microbiome is known to influence the pathogenesis and progression of neurodegenerative diseases. However, there has been relatively little focus upon the implications of the gut microbiome in retinal diseases such as retinitis pigmentosa (RP) that leads to photoreceptor degeneration and is the main worldwide cause of complete blindness in adulthood. Here, we investigated changes in gut microbiome composition linked to RP, by assessing both retinal degeneration and gut microbiome in the rd10 mouse model of RP as compared to control C57BL/6J mice.Results: In rd10 mice, retinal responsiveness to flashlight stimuli was deteriorated with respect to observed in age-matched control mice, with decreased amplitudes in the a- and b-wave responses of the electroretinogram and concomitant reduction of the visual acuity. This functional decline in dystrophic animals was accompanied by photoreceptor loss, evidenced by decreased outer nuclear layer thickness, and morphologic anomalies in photoreceptor cells. Changes in retinal neurons were paralleled to induction of reactive gliosis in retina, with increased microglial cell numbers and higher Müller cell reactivity in rd10 mice. Furthermore, 16S rRNA gene amplicon sequencing data showed a microbial gut dysbiosis with differences in alpha and beta diversity at the genera, species and amplicon sequence variants (ASV) levels between dystrophic and control mice. A taxonomic partitioning of ASV was observed since unique ASVs present in only one group had a cumulative relative microbial abundance between 17.6% (rd10 mice) and 26.7% (C57BL/6J mice). Remarkably, four fairly common ASV in healthy gut microbiome belonging to -Rikenella spp., Muribaculaceace spp., Prevotellaceae UCG-001 spp., and Bacilli spp.- were absent in the gut microbiome of retinal disease mice, while Bacteroides caecimuris was significantly enriched in mice with retinitis pigmentosa. Conclusions: Our results indicate that retinal degenerative changes in retinitis pigmentosa are linked to relevant gut microbiome changes. The findings suggest that microbiome shifting could be considered as potential biomarker and therapeutic target for retinal degenerative diseases.

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Immunosuppression, peripheral inflammation and invasive infection from endogenous gut microbiota activate retinal microglia in mouse models

Cited by 11 publications

References 42 publications

Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy

Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy

Physical Exercise Inhibits Inflammation and Microglial Activation

Retinitis Pigmentosa Is Associated With Shifts in The Gut Microbiome

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