Damage-associated molecular pattern recognition is required for induction of retinal neuroprotective pathways in a sex-dependent manner

Hooper, Marcus; Wang, Jiangang; Browning, Robert; Ash, John D.

doi:10.1038/s41598-018-27479-x

Cited by 7 publications

(5 citation statements)

References 56 publications

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“…DAMPs have dual roles in the retina; e.g., fractalkine, which has been reported as a DAMP, is neuroprotective in rd10 retinas by signaling through its CX3CR1 receptor, preventing microglia-induced damage (Roche et al, 2016). Stressed photoreceptors release DAMPs early in degeneration to induce neuroprotective responses in retinal glial cells by interacting with receptors as Toll-like receptor 2, a DAMP receptor that increases in Müller glial cells during degeneration (Hooper et al, 2018). S1P promotes migration in Müller glial cells and RPE cells (Swaney et al, 2008; Simón et al, 2015), which might release it to the retina milieu to act as an autocrine signal and promote a fibrotic process and/or to act as a paracrine signal in photoreceptors, promoting neuroprotection.…”

Section: Sphingosine-1-phosphate a Formidable Double-edged Sword In mentioning

confidence: 99%

Sphingolipids as Emerging Mediators in Retina Degeneration

Simón

Spalm

Vera

et al. 2019

Front. Cell. Neurosci.

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The sphingolipids ceramide (Cer), sphingosine-1-phosphate (S1P), sphingosine (Sph), and ceramide-1-phosphate (C1P) are key signaling molecules that regulate major cellular functions. Their roles in the retina have gained increasing attention during the last decade since they emerge as mediators of proliferation, survival, migration, neovascularization, inflammation and death in retina cells. As exacerbation of these processes is central to retina degenerative diseases, they appear as crucial players in their progression. This review analyzes the functions of these sphingolipids in retina cell types and their possible pathological roles. Cer appears as a key arbitrator in diverse retinal pathologies; it promotes inflammation in endothelial and retina pigment epithelium (RPE) cells and its increase is a common feature in photoreceptor death in vitro and in animal models of retina degeneration; noteworthy, inhibiting Cer synthesis preserves photoreceptor viability and functionality. In turn, S1P acts as a double edge sword in the retina. It is essential for retina development, promoting the survival of photoreceptors and ganglion cells and regulating proliferation and differentiation of photoreceptor progenitors. However, S1P has also deleterious effects, stimulating migration of Müller glial cells, angiogenesis and fibrosis, contributing to the inflammatory scenario of proliferative retinopathies and age related macular degeneration (AMD). C1P, as S1P, promotes photoreceptor survival and differentiation. Collectively, the expanding role for these sphingolipids in the regulation of critical processes in retina cell types and in their dysregulation in retina degenerations makes them attractive targets for treating these diseases.

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Section: Sphingosine-1-phosphate a Formidable Double-edged Sword In mentioning

confidence: 99%

Sphingolipids as Emerging Mediators in Retina Degeneration

Simón

Spalm

Vera

et al. 2019

Front. Cell. Neurosci.

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“…As TLR2 is mainly expressed by retinal microglial cells [ 18 , 19 ] and microglia are the primary reactive cells to retinal damage [ 20 , 21 ], we next investigated whether Tlr2 deletion affected the microglial response to RP. We used flow cytometry to analyze the retinal myeloid population in the rd10 model, in which we had previously characterized the temporal pattern of microglial activation [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

“…Beneficial effects of targeting TLR2 have also been described in animal models of other neurodegenerative pathologies of the CNS, including Alzheimer’s and Parkinson’s diseases [ 35 , 36 ]. However, Hooper et al found that genetic deletion of Tlr2 worsened light-induced retinal damage in an albino mouse model [ 19 ]. While the reasons for the discrepancies between our findings and others, and those of the latter study are not clear, differences in the type of insult and the genetic background could contribute to the divergent outcomes, as well as the fact Hooper et al used non-pigmented mice.…”

Section: Discussionmentioning

confidence: 99%

Tlr2 Gene Deletion Delays Retinal Degeneration in Two Genetically Distinct Mouse Models of Retinitis Pigmentosa

Sánchez-Cruz

Méndez

Lizasoaín

et al. 2021

IJMS

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Although considered a rare retinal dystrophy, retinitis pigmentosa (RP) is the primary cause of hereditary blindness. Given its diverse genetic etiology (>3000 mutations in >60 genes), there is an urgent need for novel treatments that target common features of the disease. TLR2 is a key activator of innate immune response. To examine its role in RP progression we characterized the expression profile of Tlr2 and its adaptor molecules and the consequences of Tlr2 deletion in two genetically distinct models of RP: Pde6brd10/rd10 (rd10) and RhoP23H/+ (P23H/+) mice. In both models, expression levels of Tlr2 and its adaptor molecules increased in parallel with those of the proinflammatory cytokine Il1b. In rd10 mice, deletion of a single Tlr2 allele had no effect on visual function, as evaluated by electroretinography. However, in both RP models, complete elimination of Tlr2 attenuated the loss of visual function and mitigated the loss of photoreceptor cell numbers. In Tlr2 null rd10 mice, we observed decreases in the total number of microglial cells, assessed by flow cytometry, and in the number of microglia infiltrating the photoreceptor layers. Together, these results point to TLR2 as a mutation-independent therapeutic target for RP.

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“…PHR degeneration modulates the expression of Neurotrophin receptor genes in retinal MGC (Harada et al, 2000). PHRs have also been reported to release stress signals, the damage-associated molecular patterns (DAMPs) during degenerative processes of the retina, that orchestrate a broad neuroprotective response in MGC, including release of Leukemia Inhibitory Factor (LIF), a critical PHR survival factor (Hooper et al, 2018). A further putative signal might be glutamate, which PHRs release as a neurotransmitter; activation of NMDA receptors has been shown to increase proliferation and differentiation of hippocampal neural progenitor cells (Joo et al, 2007) and might have a similar effect on retinal MGC.…”

Section: Discussionmentioning

confidence: 99%

A Defective Crosstalk Between Neurons and Müller Glial Cells in the rd1 Retina Impairs the Regenerative Potential of Glial Stem Cells

Volonté

Vallese-Maurizi

Dibo

et al. 2019

Front. Cell. Neurosci.

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Müller glial cells (MGC) are stem cells in the retina. Although their regenerative capacity is very low in mammals, the use of MGC as stem cells to regenerate photoreceptors (PHRs) during retina degenerations, such as in retinitis pigmentosa, is being intensely studied. Changes affecting PHRs in diseased retinas have been thoroughly investigated; however, whether MGC are also affected is still unclear. We here investigated whether MGC in retinal degeneration 1 ( rd1 ) mouse, an animal model of retinitis pigmentosa, have impaired stem cell properties or structure. rd1 MGC showed an altered morphology, both in culture and in the whole retina. Using mixed neuron-glial cultures obtained from newborn mice retinas, we determined that proliferation was significantly lower in rd1 than in wild type (wt) MGC. Levels of stem cell markers, such as Nestin and Sox2 , were also markedly reduced in rd1 MGC compared to wt MGC in neuron-glial cultures and in retina cryosections, even before the onset of PHR degeneration. We then investigated whether neuron-glial crosstalk was involved in these changes. Noteworthy, Nestin expression was restored in rd1 MGC in co-culture with wt neurons. Conversely, Nestin expression decreased in wt MGC in co-culture with rd1 neurons, as occurred in rd1 MGC in rd1 neuron-glial mixed cultures. These results imply that MGC proliferation and stem cell markers are reduced in rd1 retinas and might be restored by their interaction with “healthy” PHRs, suggesting that alterations in rd1 PHRs lead to a disruption in neuron-glial crosstalk affecting the regenerative potential of MGC.

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Damage-associated molecular pattern recognition is required for induction of retinal neuroprotective pathways in a sex-dependent manner

Cited by 7 publications

References 56 publications

Sphingolipids as Emerging Mediators in Retina Degeneration

Sphingolipids as Emerging Mediators in Retina Degeneration

Tlr2 Gene Deletion Delays Retinal Degeneration in Two Genetically Distinct Mouse Models of Retinitis Pigmentosa

A Defective Crosstalk Between Neurons and Müller Glial Cells in the rd1 Retina Impairs the Regenerative Potential of Glial Stem Cells

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