C-reactive protein inhibits pneumococcal activation of the alternative pathway by increasing the interaction between factor H and C3b.

Abstract

We previously studied two alternative pathway activators, Streptococcus pneumoniae and positively charged liposomes, which react with C-reactive protein (CRP). Binding of CRP to these surfaces initiates classical pathway but blocks alternative pathway activation. In this study, we investigated the mechanism of this inhibition using S. pneumoniae, R36a. R36a were pretreated with CRP (CRP-R36a) or buffer and incubated with C2-deficient human serum to which 125I-labeled C3 had been added. The amount of specific 125I-C3 binding was decreased from 8200 mol/CFU on R36a to 2200 mol/CFU on CRP-R36a. In contrast, when the same experiment was performed with purified factors B, D, P, and C3, in the absence of regulatory proteins, specific 125I-C3 uptake was slightly lower on R36a (6100 mol/CFU) than on CRP-R36a (8100 mol/CFU). The ability of the fixed C3b to inactivate factor B in the presence of factor D was equivalent on the two surfaces. The binding of the regulatory factor H to C3b fixed to R36a and CRP-R36a was compared by using purified 125I-labeled factor H. The ratio of factor H bound to C3 bound was twofold greater on CRP-R36a than on R36a. This increase was found by using C2-deficient serum or purified factors B, D, P, and C3 to fix C3b to the surfaces. The ability of CRP to inhibit C3 binding to R36a was restored by the addition of factors H and I to factors B, D, P, and C3. These results indicate that CRP inhibits alternative pathway activation by increasing regulation of bound C3.

Mitochondrial damage and clearance in retinal pigment epithelial cells

“…FH, which is involved in regulating the CS, has been found to have a positive correlation with CRP levels (Chirco & Potempa, 2018; Lu et al., 2020). Additionally, CRP has been shown to inactivate the AP of the CS (Jarva et al., 1999; Mold et al., 1984). We analysed CRP levels in both dKO and WT retinas and found a statistically significant 150% increase in CRP levels (Figure 27c) in the INL, ONL and RPE layers of the dKO retina when compared to the WT retina (Appendix , Figure B3).…”

“…CRP, a major acute phase protein, is known to regulate complement activation by binding FH and has been associated with AMD (Colak et al., 2012; Mold et al., 1984; Seddon et al., 2004; Wang, Lu, et al., 2018). Moreover, ligands for CRP are known to directly activate TLRs (Lu et al., 2018), and a TLR3 deficiency impairs the expression of both CRP and IL‐6 (Lo Gullo et al., 2014).…”

Latest Development on Genetics of Common Retinal Diseases

“…The first AMD locus was mapped to chromosome 1q25–q31 by genome-wide linkage analysis in a pedigree of AMD 9. It was later confirmed as the locus that harbors an important AMD-associated gene, complement factor H ( CFH ), which mainly involved in the complement pathway and alternative pathway 10,11. This finding laid the foundation for future genetic analysis of AMD.…”

A biofunctional review of C-reactive protein (CRP) as a mediator of inflammatory and immune responses: differentiating pentameric and modified CRP isoform effects

“…To limit inflammatory responses to the damaged area, CRP also influences alternative complement pathway (AP) activity, downregulating deposition of C3b on AP-activating surfaces, decreasing C3 and C5 convertase activity and inhibiting C amplification feedback ( 20 ). In particular, on stearylamine-containing liposomes and on Types 6 and R36a Streptococcal pneumonia surfaces, CRP decreased serum C3-activation implicating CRP as a regulatory protein that can limit the extent of inflammatory damage initiated by C activation ( 69 , 102 ). Taken together, CRP binding to damaged membrane or bacterial surfaces can preference the immune response towards classical pathway activation and away from the AP ( 102 ).…”

“…In particular, on stearylamine-containing liposomes and on Types 6 and R36a Streptococcal pneumonia surfaces, CRP decreased serum C3-activation implicating CRP as a regulatory protein that can limit the extent of inflammatory damage initiated by C activation ( 69 , 102 ). Taken together, CRP binding to damaged membrane or bacterial surfaces can preference the immune response towards classical pathway activation and away from the AP ( 102 ). AP inhibitory activity was found to be Factor H dependent, with direct binding of Factor H to CRP implicated through ELISA experimentation.…”