Systemic and Ocular Long Pentraxin 3 in Patients with Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) has been associated with both systemic and ocular alterations of the immune system. In particular dysfunction of complement factor H (CFH), a soluble regulator of the alternative pathway of the complement system, has been implicated in AMD pathogenesis. One of the ligands for CFH is long pentraxin 3 (PTX3), which is produced locally in the retinal pigment epithelium (RPE). To test the hypothesis that PTX3 is relevant to retinal immunohomeostasis and may be associated with AMD pathogenesis, we measured plasma PTX3 protein concentration and analyzed the RPE/choroid PTX3 gene expression in patients with AMD. To measure the ability of RPE cells to secrete PTX3 in vitro, polarized ARPE-19 cells were treated with activated T cells or cytokines (interferon (IFN)-gamma and/or tumor necrosis factor (TNF)-alpha) from the basolateral side; then PTX3 protein concentration in supernatants and PTX3 gene expression in tissue lysates were quantified. Plasma levels of PTX3 were generally low and did not significantly differ between patients and controls (P=0.307). No statistically significant difference was observed between dry and exudative AMD nor was there any correlation with hsCRP or CFH genotype. The gene expression of PTX3 increased in RPE/choroid with age (P=0.0098 macular; P=0.003 extramacular), but did not differ between aged controls and AMD patients. In vitro, ARPE-19 cells increased expression of the PTX3 gene as well PTX3 apical secretions after stimulation with TNF-alpha or activated T cells (P<0.01). These findings indicate that PTX3 expressed in the eye cannot be detected systemically and systemic PTX3 may have little or no impact on disease progression, but our findings do not exclude that locally produced PTX3 produced in the posterior segment of the eye may be part of the AMD immunopathogenesis.

C-reactive protein and pentraxin-3 binding of factor H-like protein 1 differs from complement factor H: implications for retinal inflammation

“…Another inflammation-associated pentraxin that has been linked with complement activation is PTX3, where FH is known to bind this long pentraxin via its CCP6-8 (via CCP7) and CCP19-20 regions 1 , 28 ; PTX3 enhances the interaction of FH with apoptotic cells leading to their increased opsonization with iC3b 28 . However, unlike CRP 27 , neither the plasma levels of PTX3 nor its gene expression in the RPE/choroid correlate with AMD status 29 . In addition, the Y402H polymorphism does not affect FH binding to PTX3 28 .…”

Inflammation and its role in age-related macular degeneration

“…Significant and moderate increases in the plasma concentrations of inflammasome-related cytokines IL-18 and IL-1β, respectively, in patients carrying the high risk CC alleles of Y402H variant raises an intriguing possibility that there is systemic or continuous inflammasome activation in patients suffering from dry AMD [ 259 ]. In addition to those factors mentioned above, there are many other inflammation-related factors, such as eotaxin, fibrinogen, IP-10, long pentraxin 3, sFasL (soluble Fas ligand), sICAM-1 (soluble intercellular adhesion molecule-1), sTNFRII (TNF-a receptor II), that have also been proposed as biomarkers of AMD [ 267 , 272 , 276 – 280 ]. Although there has been increased research in obtaining reliable biomarkers for AMD, no selective blood biomarker has been found that meets the requirements of early AMD detection.…”

Monomeric C-reactive protein and inflammation in age-related macular degeneration

“…Another inflammatory risk factor associated with AMD is elevated serum C‐reactive protein (CRP), which has long been studied as a marker of systemic inflammation. As a member of the pentraxin protein family, which includes AMD‐associated PTX3 , CRP is an acute phase protein predominantly produced in the liver and released into circulation upon stimulation by IL‐6 and other cytokines . CRP primarily exists in two structurally and functionally independent forms: (1) net anti‐inflammatory, serum‐associated pentameric CRP (pCRP), and (2) pro‐inflammatory tissue‐associated, monomeric CRP (mCRP).…”

“…Another inflammatory risk factor associated with AMD is elevated serum C-reactive protein (CRP), which has long been studied as a marker of systemic inflammation. As a member of the pentraxin protein family, which includes AMD-associated PTX3 [9], CRP is an 174 KR Chirco et al anti-inflammatory, serum-associated pentameric CRP (pCRP), and (2) pro-inflammatory tissue-associated, monomeric CRP (mCRP). Within 8-72 h of the onset of an inflammatory response, serum pCRP concentrations have been shown to increase from less than 3 μg/ml to more than 100 μg/ml [11][12][13].…”