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

Abstract

Retinal inflammation plays a key role in the progression of age-related macular degeneration (AMD), a condition that leads to loss of central vision. The deposition of the acute phase pentraxin C-reactive protein (CRP) in the macula activates the complement system, thereby contributing to dysregulated inflammation. The complement protein factor H (FH) can bind CRP and down-regulate an inflammatory response. However, it is not known whether a truncated form of FH, called factor H-like protein 1 (FHL-1), which plays a significant regulatory role in the eye, also interacts with CRP. Here, we compare the binding properties of FHL-1 and FH to both CRP and the related protein pentraxin-3 (PTX3). We find that, unlike FH, FHL-1 can bind pro-inflammatory monomeric CRP (mCRP) as well as the circulating pentameric form. Furthermore, the four-amino acid C-terminal tail of FHL-1 (not present in FH) plays a role in mediating its binding to mCRP. PTX3 was found to be present in the macula of donor eyes and the AMD-associated Y402H polymorphism altered the binding of FHL-1 to PTX3. Our findings reveal that the binding characteristics of FHL-1 differ from those of FH, likely underpinning independent immune regulatory functions in the context of the human retina.

Extracellular Vesicles: Packages Sent With Complement

“…On the other hand, MVs bound with pCRP*/mCRP may recruit FI, FH, and/or FHL-1, which in turn processes the bound or circulating C3b to iC3b. Interestingly, a current study revealed that the complement regulator FHL-1 is able to bind pCRP as well as mCRP, and FH is able to bind mCRP ( 110 ). Since pCRP* also expresses a neoepitope, it can be speculated, that pCRP/pCRP* and/or mCRP, which are bound on MVs support FH and FHL-1 recruitment, which in turn enhances the processing of C3b to iC3b.…”

Evaluation of serum sphingolipids and the influence of genetic risk factors in age-related macular degeneration

“…Therefore, it may be possible that FHL-1 promotes regulation of the ceramide metabolism in WERI-Rb1 cells in a membrane receptor-dependent manner using the RGD motif and triggering an intracellular response, which may explain our observation that both FHL-1 variants statistically decreased the gene expression of SGMS1 and SPTLC1 compared to PBS control. Moreover, a recent study has shown that the binding of FHL-1 to C-reactive protein and pentraxin-3 differs from the binding of CFH to these proteins, and that the interaction between FHL-1 and pentraxin-3 is altered by the Y402H polymorphism [ 80 ]. These results show that FHL-1 has binding abilities different from CFH that are influenced by the Y402H variant.…”

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

“…This gap in knowledge is surprising, given that both CRP and SAP are ligands of C1q, and can activate the CP cascade [112,113]. Furthermore, CRP and SAP exert complement regulating activities through specific interactions with factor H [114,115] and C4BP [116], respectively, where these inhibitors are regarded as major targets for complement evasion by A. fumigatus (see above). Also, SAP is a binder of major ECM components, including type IV collagen [117] and fibronectin [118], which have been implicated in the initial adhesion of dormant conidia to the lung epithelium [119,120], and both short pentraxins recognize FccRs and participate in the FccR-dependent phagocytosis of microbes (and apoptotic cells) by phagocytic cells [121].…”