Pentraxin 3 recruits complement factor H to protect against oxidative stress-induced complement and inflammasome overactivation

The discovery that genetic abnormalities in complement factor H (FH) are associated with 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 innate immunity 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, resulting from PTX3 deficiency, raised levels of Il1b mRNA and secretion of activated l1b by interacting with C3aR. Importantly, PTX3 deficiency augmented NLRP3 inflammasome activation resulting in enhanced IL-1b, but not IL-18 production by the RPE. Thus, with PTX3 deficiency, the complement and inflammasome pathways worked in concert to produce IL-1b in sufficient abundance that importantly, resulted 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 insight into the complex interplay between oxidative stress and innate immunity in the early stages of AMD development.