title: Pentraxin 3 recruits complement factor H to protect against oxidative stress-induced complement and inflammasome overactivation.
abstract: The discovery that genetic abnormalities in complement factor H (FH) are associated with an increased risk for age-related macular degeneration (AMD), the most common cause of blindness among the elderly, raised hope of new treatments for this vision-threatening disease. Nonetheless, over a decade after the identification of this important association, how innate immunity contributes to AMD remains unresolved. Pentraxin 3 (PTX3), an essential component of the innate immunity system that plays a non-redundant role in controlling inflammation, regulates complement by interacting with complement components. Here, we show that PTX3 is induced by oxidative stress, a known cause of AMD, in the retinal pigmented epithelium (RPE). PTX3 deficiency in vitro and in vivo magnified complement activation induced by oxidative stress, leading to increased C3a, FB, and C3d, but not C5b-9 complex formation. Increased C3a levels, resulting from PTX3 deficiency, raised the levels of Il1b mRNA and secretion of activated interleukin (IL)-1β by interacting with C3aR. Importantly, PTX3 deficiency augmented NLRP3 inflammasome activation, resulting in enhanced IL-1β, but not IL-18, production by the RPE. Thus, in the presence of PTX3 deficiency, the complement and inflammasome pathways worked in concert to produce IL-1β in sufficient abundance to, importantly, result in macrophages accumulating in the choroid. These results demonstrate that PTX3 acts as an essential brake for complement and inflammasome activation by regulating the abundance of FH in the RPE, and provide critical insights into the complex interplay between oxidative stress and innate immunity in the early stages of AMD development. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, USA.
authors.forename: Marisol
authors.initials: M
authors.lastname: Cano
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, USA.
authors.forename: Sayantan
authors.initials: S
authors.lastname: Datta
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wei
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, USA.
authors.forename: Katayoon B
authors.initials: KB
authors.lastname: Ebrahimi
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, USA.
authors.forename: Yara
authors.initials: Y
authors.lastname: Gorashi
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico-Humanitas Clinical and Research Centre, Milan, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Handa
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D002097:C-Reactive Protein / Q000172:deficiency / Q000276:immunology*; D002478:Cells, Cultured; D002829:Choroid / Q000276:immunology; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology; D015926:Complement C3a / Q000276:immunology; D017242:Complement Factor H / Q000276:immunology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D008268:Macular Degeneration / Q000276:immunology*; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000276:immunology*; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D055213:Retinal Pigment Epithelium / Q000276:immunology; D000099153:Pentraxins
chemical_list: D000447:Aldehydes; D002097:C-Reactive Protein; D015926:Complement C3a; D017242:Complement Factor H; D015853:Cysteine Proteinase Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; D000099153:Pentraxins; C027576:4-hydroxy-2-nonenal
keywords: age-related macular degeneration; complement; inflammasome; innate immunity; pentraxin 3; retinal pigmented epithelium