Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration.

Matteo Stravalaci,Antonio Inforzato,Alberto Mantovani,Barbara Bottazzi,Raffaella Parente,Simon J Clark,Anthony J Day,Marco Gobbi,Mario R Romano,Francesca Davi

doi:10.3389/fphar.2020.591908

Abstract

Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H (CFH) gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a “hot spot” for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.

Highlights

Age-related macular degeneration (AMD) is a neurodegenerative and multifactorial disease of the eye that distinctively manifests itself with ageing (Jager et al, 2008), and is recognized as the leading cause of irreversible visual impairment in the elderly (Wong et al, 2014)
We evaluated whether inflammatory AMD-like conditions could induce changes in the expression of soluble components of the alternative pathway (AP) and membraneassociated complement inhibitors in ARPE-19 cells
CD59 mRNA (Figure 1G) was upregulated in ARPE-19 cells treated with TNF-α, but not IL-1β

Summary

Introduction

Age-related macular degeneration (AMD) is a neurodegenerative and multifactorial disease of the eye that distinctively manifests itself with ageing (Jager et al, 2008), and is recognized as the leading cause of irreversible visual impairment in the elderly (Wong et al, 2014). The rs1061170 single nucleotide polymorphism (SNP) in the complement factor H (CFH) gene (that leads to the Y402H amino acid substitution in the protein) has a strong association with the disease Edwards et al (2005), Hageman et al (2005), Haines et al (2005). The Y402H polymorphism (in CCP7) alters the binding of FH to heparan sulfate (in the BrM) (Parente et al, 2017; Clark and Bishop, 2018) and C reactive protein (CRP, which is present both in the BrM and choroid) (Sjoberg et al, 2007), leading to inappropriate complement activation and complementdriven inflammation, with pathological progression to AMD (Clark and Bishop, 2018)

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Conclusion