Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization

Malsy, Jakob; Alvarado, Andrea C; Lamontagne, Joseph O; Strittmatter, Karin; Marneros, Alexander G.

doi:10.7554/elife.60194

Cited by 21 publications

(34 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Substantial evidence in the literature suggests the activation of NLRP3 inflammasome in retinal degeneration through a significant augmentation in the inflammasome components, including NLRP3 , ASC , and CASP1 [ 30 , 31 , 32 ]. The caspase-1-dependent pro-inflammatory cytokines, such as IL-1β and IL-18 are also activated in retinal degenerative conditions [ 33 ].…”

Section: Factors Contributing To Inflammation In Retinal Degenerative Diseasesmentioning

confidence: 99%

The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases

Kaur

Singh

2021

IJMS

View full text Add to dashboard Cite

Retinal neurodegeneration is predominantly reported as the apoptosis or impaired function of the photoreceptors. Retinal degeneration is a major causative factor of irreversible vision loss leading to blindness. In recent years, retinal degenerative diseases have been investigated and many genes and genetic defects have been elucidated by many of the causative factors. An enormous amount of research has been performed to determine the pathogenesis of retinal degenerative conditions and to formulate the treatment modalities that are the critical requirements in this current scenario. Encouraging results have been obtained using gene therapy. We provide a narrative review of the various studies performed to date on the role of inflammation in human retinal degenerative diseases such as age-related macular degeneration, inherited retinal dystrophies, retinitis pigmentosa, Stargardt macular dystrophy, and Leber congenital amaurosis. In addition, we have highlighted the pivotal role of various inflammatory mechanisms in the progress of retinal degeneration. This review also offers an assessment of various therapeutic approaches, including gene-therapies and stem-cell-based therapies, for degenerative retinal diseases.

show abstract

Section: Factors Contributing To Inflammation In Retinal Degenerative Diseasesmentioning

confidence: 99%

The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases

Kaur

Singh

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Specifically, the dysregulation of complement factors, such as complement factor H (CFH) and complement component (C3), have been associated with progression to GA [7,8]. Dysregulation of complement factors can also cause inflammasome activation in the RPE and activation of microglia [9]. During disease progression, microglia can migrate to the subretinal space and release proinflammatory cytokines that contribute to CNV [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Dysregulation of complement factors can also cause inflammasome activation in the RPE and activation of microglia [9]. During disease progression, microglia can migrate to the subretinal space and release proinflammatory cytokines that contribute to CNV [9][10][11]. However, animal models based on these risk factors do not fully explain the disease etiology [12,13], suggesting that there are other unknown factors that participate in the development of AMD.…”

Section: Introductionmentioning

confidence: 99%

HK2 Mediated Glycolytic Metabolism in Mouse Photoreceptors Is Not Required to Cause Late Stage Age-Related Macular Degeneration-Like Pathologies

et al. 2021

View full text Add to dashboard Cite

Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein TSC1. Here, we confirm our previous findings by deletion of the other complex protein, namely TSC2, in rod photoreceptors. Similar to deletion of Tsc1, mice with deletion of Tsc2 in rods develop AMD-like pathologies, including accumulation of apolipoproteins, migration of microglia, geographic atrophy, and neovascular pathologies. Subtle differences between the two mouse models, such as a significant increase in microglia activation with loss of Tsc2, were seen as well. To investigate the role of altered glucose metabolism in disease pathogenesis, we generated mice with simulation deletions of Tsc2 and hexokinase-2 (Hk2) in rods. Although retinal lactate levels returned to normal in mice with Tsc2-Hk2 deletion, AMD-like pathologies still developed. The data suggest that the metabolic adaptations in PRs that cause AMD-like pathologies are independent of HK2-mediated aerobic glycolysis.

show abstract

“…NLRP3 in ammasome activation in non-RPE cells, but not in RPE cells, promotes CNV in an nAMD mouse model [20]. However, NNLRP3 in ammasome activation occurs in macrophages and results in IL-18 activation, which inhibits laser-induced CNV [11].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk Between RPE Cells and Choroidal Endothelial Cells via the ANXA1/FPR2/SHP2/NLRP3 Inflammasome/Pyroptosis Axis Promotes Choroidal Neovascularization

et al. 2021

View full text Add to dashboard Cite

One type of age-related macular degeneration (AMD), neovascular (nAMD), characterized by choroidal neovascularization (CNV), accounts for the majority of the severe central vision impairment associated with AMD. Endothelial cells (ECs) in direct contact with retinal pigment epithelial (RPE) cells are more prone to the pathological angiogenesis involved in CNV. Herein, we investigated the effect of crosstalk between RPE cells and choroidal endothelial cells (CECs) via the ANXA1/FPR2/NLRP3 in ammasome/pyroptosis axis on the development of choroidal neovascularization (CNV) in vitro and in vivo. ANXA1 expression and secretion from ARPE-19 cells were upregulated by hypoxia. FPR2 expression, especially on the plasma membrane, in HCECs was upregulated under hypoxic conditions. ANXA1 secreted from ARPE-19 cells inhibited NLRP3 in ammasome activation and NLRP3 in ammasomemediated pyroptosis in HCECs by activating the FPR2/SHP2 axis. Moreover, ANXA1 secreted by ARPE-19 cells promoted behaviors of HCECs, including proliferation, migration and tube formation, by activating the FPR2/SHP2 axis and inhibiting NLRP3 in ammasome-mediated pyroptosis. Inhibiting the upregulated ANXA1/FPR2/SHP2/NLRP3 in ammasome/pyroptosis axis decreased the volume of CNV.Our data suggest that the crosstalk between RPE cells and CECs via the ANXA1/FPR2/NLRP3 in ammasome/pyroptosis axis promotes CNV. This nding could identify a potential target for the prevention and treatment of CNV.

show abstract

Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization

Cited by 21 publications

References 41 publications

The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases

The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases

HK2 Mediated Glycolytic Metabolism in Mouse Photoreceptors Is Not Required to Cause Late Stage Age-Related Macular Degeneration-Like Pathologies

Crosstalk Between RPE Cells and Choroidal Endothelial Cells via the ANXA1/FPR2/SHP2/NLRP3 Inflammasome/Pyroptosis Axis Promotes Choroidal Neovascularization

Contact Info

Product

Resources

About