Inhibition of the alternative complement pathway preserves photoreceptors after retinal injury

Sweigard, J. Harry; Matsumoto, Hidetaka; Smith, Kaylee E.; Kim, Leo A.; Paschalis, Eleftherios I.; Okonuki, Yoko; Castillejos, Alexandra; Kataoka, Keiko; Hasegawa, Eiichi; Yanai, Ryoji; Husain, Deeba; Lambris, John D.; Vavvas, Demetrios G.; Miller, Joan W.; Connor, Kip M.

doi:10.1126/scitranslmed.aab1482

Cited by 43 publications

(44 citation statements)

References 59 publications

(98 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…With this in mind, our anti-CFD data indicate that photoreceptors are sensitive to C3 deposition/opsonization whereas the RPE may be more sensitive to the effects of amplifying the AP. Indeed, others have shown that complement regulators Cd55/ Cd59 are reduced specifically in the photoreceptors in a model of retinal detachment, making photoreceptors especially sensitive to opsonization and complement-mediated death (Sweigard et al, 2015). By contrast, the fact that TLR2 deficiency protected both photoreceptor numbers and the RPE implies that, in response to oxidative stress, TLR2 signaling promotes both C3 opsonization and the amplification of the AP.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpressing C3 in the retina can promote many features of AMD (Cashman et al, 2011;Rohrer et al, 2007), while inhibiting various complement factors can protect against photoreceptor cell death in models of retinal degeneration (Sweigard et al, 2015;Rohrer et al, 2007). To define a role for TLR2 in bridging oxidative stress to complement activation and assessing its function in retinal degeneration, we utilized a well-characterized light-induced photo-oxidative stress model of retinal degeneration in which locally produced C3 is known to contribute causally to retinal degeneration (Natoli et al, 2017).…”

Section: Neutralization Of Tlr2 In a Photo-oxidative Stress Model Of mentioning

confidence: 99%

“…The common, coding variant Y402H in the complement factor H (CFH) gene is strongly associated with influencing susceptibility to AMD (Klein et al, 2005) and increasing severity of GA (Seddon et al, 2007). In fact, the role of complement in the retina is a topic of intense investigation, as it contributes to a variety of other retinal disease pathologies in addition to AMD (Sweigard et al, 2015;Sweigard et al, 2014;Kim et al, 2016). Variants in other complement-related genes are associated with AMD risk, including C3, CFI, and C9 (Yates et al, 2007;Despriet et al, 2009;van de Ven et al, 2013;Seddon et al, 2013); all result in an overly active complement system.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration

et al. 2020

View full text Add to dashboard Cite

Graphical Abstract Highlights d TLR2 activates the alternative complement pathway d TLR2 signaling triggers sub-lytic MAC formation on retinal pigment epithelial cells d TLR2 deficiency reduces oxidative stress-induced C3 and MAC in the outer retina d TLR2 blockade protects photoreceptors and RPE from oxidative stress-induced cell death SUMMARY Retinal degeneration is a form of neurodegenerative disease and is the leading cause of vision loss globally. The Toll-like receptors (TLRs) are primary components of the innate immune system involved in signal transduction. Here we show that TLR2 induces complement factors C3 and CFB, the common and rate-limiting factors of the alternative pathway in both retinal pigment epithelial (RPE) cells and mononuclear phagocytes. Neutralization of TLR2 reduces opsonizing fragments of C3 in the outer retina and protects photoreceptor neurons from oxidative stress-induced degeneration. TLR2 deficiency also preserves tight junction expression and promotes RPE resistance to fragmentation. Finally, oxidative stress-induced formation of the terminal complement membrane attack complex and Iba1+ cell infiltration are strikingly inhibited in the TLR2-deficient retina. Our data directly implicate TLR2 as a mediator of retinal degeneration in response to oxidative stress and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Neutralization Of Tlr2 In a Photo-oxidative Stress Model Of mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration

et al. 2020

View full text Add to dashboard Cite

show abstract

“…as malondialdehyde activate complement (18); subretinal drusen from AMD patients have complement components (16); and retinal detachment down-regulates CD59, leading to MAC deposition in the photoreceptor-RPE region (19).…”

Section: Significancementioning

confidence: 99%

Protective responses to sublytic complement in the retinal pigment epithelium

Tan

Toops

Lakkaraju

2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration. Using polarized primary RPE and the pigmented Abca4 −/− Stargardt disease mouse model, we provide evidence for two protective responses occurring within minutes of complement attack, which are essential for maintaining mitochondrial health in the RPE. First, accelerated recycling of the membrane-bound complement regulator CD59 to the RPE cell surface inhibits MAC formation. Second, fusion of lysosomes with the RPE plasma membrane immediately after complement attack limits sustained elevations in intracellular calcium and prevents mitochondrial injury. Cholesterol accumulation in the RPE, induced by vitamin A dimers or oxidized LDL, inhibits these defense mechanisms by activating acid sphingomyelinase (ASMase), which increases tubulin acetylation and derails organelle traffic. Defective CD59 recycling and lysosome exocytosis after complement attack lead to mitochondrial fragmentation and oxidative stress in the RPE. Drugs that stimulate cholesterol efflux or inhibit ASMase restore both these critical safeguards in the RPE and avert complement-induced mitochondrial injury in vitro and in Abca4 −/− mice, indicating that they could be effective therapeutic approaches for macular degenerations.he complement system is an important regulator of immunity and inflammation. Complement activation by the classical, alternative, or lectin pathways results in the assembly of C5b-9 membrane attack complexes (MACs), which form membrane pores and cause target cell lysis. Within the eye, a low level of constant complement activity is necessary for immune surveillance, and several membrane-bound and soluble regulators prevent excessive complement activation (1). An imbalance between complement activation and inhibition in the retina is implicated in the pathogenesis of age-related macular degeneration (AMD), which causes central vision loss in more than 30 million people globally (reviewed in refs. 2-4).Evidence suggests that the retinal pigment epithelium (RPE), which helps maintain ocular immune privilege, is the first line of defense against unregulated complement activation in the retina (5). The complement cascade is activated by insults that disturb RPE homeostasis, including defective clearance of phagocytosed photoreceptor outer segments (6) and abnormal accumulation of vitamin A dimers (7-9) or oxidized lipids (10) in the RPE. Studies also show that exposure to sublytic levels of MAC alters RPE barrier integrity, causes...

show abstract

“…However, corresponding to the diversity of complement-related effector functions, the net impact of complement activation on neural outcomes has been quite varied, with complement inhibition by genetic or pharmacological means producing both positive and negative outcomes depending on the context. In the majority of studies, complement activation has been associated with exacerbated neurodegeneration; genetic and/or pharmacological inhibition of complement components, such as C1q (37, 38), C3 (22,(39)(40)(41), CFB and CFD (42), have decreased retinal neurodegeneration, while genetic ablation complement components in models of Alzheimer's disease (AD) (29,43) and frontotemporal dementia (44), have decreased neural loss in the brain.…”

Section: Discussionmentioning

confidence: 99%

Complement C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

Silverman

Wang

et al. 2018

Preprint

View full text Add to dashboard Cite

One Sentence Summary:Complement activation mediates adaptive neuroprotection for photoreceptors by facilitating C3-CR3 dependent microglial clearance of apoptotic cells. Abstract:Complement activation has been implicated as an inflammatory driver of neurodegeneration in retinal and brain pathologies. However, its involvement and influence of photoreceptor degeneration in retinitis pigmentosa (RP), an inherited, largely incurable blinding disease, is unclear. We discover that markedly upregulated retinal expression of multiple complement components coincided spatiotemporally with photoreceptor degeneration in both the rd10 mouse model and in human specimens of RP, with increased complement C3 expression and activation localizing to infiltrating microglia near photoreceptors. Genetic ablation of C3 in the rd10 background resulted in accelerated structural and functional photoreceptor degeneration and altered retinal expression of inflammatory genes. These effects were phenocopied by the genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product C3b, implicating an adaptive microglial-mediation mechanism involving C3-CR3 interaction. Deficiency of either C3 or CR3 resulted in deficient microglial phagocytosis of apoptotic photoreceptors in vivo, as well as increased microglial neurotoxicity to photoreceptors in vitro. These findings demonstrate a novel adaptive role for complement activation in RP that facilitates microglial clearance of apoptotic photoreceptors, without which increased proinflammatory microglial neurotoxicity ensues. These positive contributions of complement via microglial-mediated mechanisms are important in the design of immunomodulatory therapeutic approaches to neurodegeneration.

show abstract

Inhibition of the alternative complement pathway preserves photoreceptors after retinal injury

Cited by 43 publications

References 59 publications

Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration

Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration

Protective responses to sublytic complement in the retinal pigment epithelium

Complement C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

Contact Info

Product

Resources

About