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

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

doi:10.3389/fphar.2020.591908

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

Front Pharmacol. 2020 Nov 26:11:591908. doi: 10.3389/fphar.2020.591908. eCollection 2020.

Authors

Matteo Stravalaci^{1

2}, Francesca Davi², Raffaella Parente², Marco Gobbi³, Barbara Bottazzi², Alberto Mantovani^{1

2

4}, Anthony J Day⁵, Simon J Clark^{6

7}, Mario R Romano^{1

8}, Antonio Inforzato^{1

2}

Affiliations

¹ Department of Biomedical Sciences, Humanitas University, Milan, Italy.
² Humanitas Clinical and Research Center IRCCS, Milan, Italy.
³ Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
⁴ The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.
⁵ Wellcome Trust Centre for Cell-Matrix Research and Lydia Becker Institute of Immunology and Inflammation, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
⁶ Universitäts-Augenklinik Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany.
⁷ The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom.
⁸ Eye Center, Humanitas Gavazzeni-Castelli, Bergamo, Italy.

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.

Keywords: age-related macular degeneration; alternative pathway; complement system; pentraxin 3; pentraxins; retinal pigmented epithelium; vitreous humor.