Complement factor H binding of monomeric C-reactive protein downregulates proinflammatory activity and is impaired with at risk polymorphic CFH variants

Abstract

Inflammation and immune-mediated processes are pivotal to the pathogenic progression of age-related macular degeneration (AMD). Although plasma levels of C-reactive protein (CRP) have been shown to be associated with an increased risk for AMD, the pathophysiological importance of the prototypical acute-phase reactant in the etiology of the disease is unknown, and data regarding the exact role of CRP in ocular inflammation are limited. In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the "risk" His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained.Age-related macular degeneration (AMD) is the primary cause of irreversible vision loss among the ageing population worldwide. The disease affects up to 1.75 million individuals alone in the United States, and this number could increase up to 3 million by 2020 [1][2][3] . Worldwide, the projected number of people with AMD in 2020 is 196 million (95% CrI 140-261), which increases to 288 million in 2040 (205-399) 4 . Local inflammation and immune-mediated processes play a central role in AMD pathogenesis 5 . Proteomic and histochemical analysis of ocular drusen, the hallmark deposits of AMD, have shown that these deposits contain inflammatory proteins and complement components that mediate local inflammation 6,7 . Furthermore, polymorphisms in a gene essential for the regulation of complement activation, CFH, are an important risk factor for developing AMD 8,9 . These and other findings have stimulated research to understand the role of immune responses in the development of the disease.C-reactive protein (CRP) is the prototypical acute-phase reactant and an active regulator of the innate immune system. It is considered to be a serum biomarker for chronic inflammation, heart disease and, more recently, AMD [10][11][12] . CRP has been identified in ocular drusen and other subretinal pigmented epithelium deposits 13,14 , as well as in the choroid, but little is known about its function in the context of AMD. Among the multiple functions ascribed to CRP are activation of the classical complement pathway and inactivation of the alternative pathway 15 . In addition, in the context of atherosclerosis, CRP upregulates the expression of adhesion molecules, and increases cytokine release from endothelial cells, neutrophils and macrophages [16][17][18] .

Complement factor H in host defense and immune evasion

“…In other studies it has been proposed that it is the monomeric (pro-inflammatory) rather than pentameric (anti-inflammatory) form of CRP that interacts with FH and, in this way, limits complement activation, increases phagocytosis of apoptotic cells and reduces the inflammatory response by macrophages [77]. Interestingly, it has been observed that the 402H variant of FH has reduced binding to monomeric CRP as compared to the 402Y allele, and, therefore, in this context, may have an impaired anti-inflammatory activity [64, 96, 97]. …”

Doyne lecture 2016: intraocular health and the many faces of inflammation

“…CFH from AMD patients carrying the 'risk' His402 polymorphism display impaired binding to mCRP, and therefore pro-inflammatory effects of mCRP remain unrestrained, at least in vitro. 69 Whether this translates to disease or not requires validation but even so alone does not account for all the immune-related changes we observe in AMD.…”

Complement Factor H as a potential atherogenic marker in chronic Chagas’ disease

“…Considering that FH binds to arterial proteoglycans deposits, 23 CRP 39 and fibromodulin, 40 and that cholesterol crystals activate complement, 41 increased FH levels in dyslipidemic CD might be a consequence of a stimulated FH secretion by adipocytes in an attempt to restrict complement driven damage during lipid metabolism dysregulation. Additionally, the FH His402 polymorphism displays impaired binding to mCRP, 42 although this was not evaluated in this study.…”