Chernyaeva L, Ratti G, Teirilä L, Fudo S, Rankka U, Pelkonen A, Korhonen P, Leskinen K, Keskitalo S, Salokas K, Gkolfinopoulou C, Crompton KE, Javanainen M, Happonen L, Varjosalo M, Malm T, Leinonen V, Chroni A, Saavalainen P, Meri S, Kajander T, Wollman AJM, Nissilä E, Haapasalo K. Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation. EMBO Reports. 2023.
Chernyaeva, Larisa and Ratti, Giorgio and Teirilä, Laura and Rankka, Uni and Fudo, Satoshi and Pelkonen, Anssi and Korhonen, Paula and Leskinen, Katarzyna and Keskitalo, Salla and Salokas, Kari and Gkolfinopoulou, Christina and Crompton, Katrina E. and Varjosalo, Markku and Malm, Tarja and Leinonen, Ville and Chroni, Angelika and Saavalainen, Päivi and Meri, Seppo and Wollman, Adam J.M. and Nissilä, Eija and Haapasalo, Karita, Reduced Binding of Apolipoprotein E4 Isoform to Complement Factor H Promotes Amyloid-Β Induced Neuroinflammation in vitro and in vivo.
Schematic presentation for how Borrelia hermsii FhbA recruits FH to mediate immune evasion. Membrane-bound BhFhbA (bright green) recruits FH (green) of the host through binding site on domain 20 of FH. When bound to BhFhbA, FH domains 1–4 are free to bind to C3b (PDB 5FO7) and inhibit complement. When bound to microbial protein via domain 20, FH can also bind C3b via domain 19.
Schematic presentation on the role of PLY and NanA in converting HDL from anti-inflammatory to pro-inflammatory and pro-atherogenic particles. Binding of PLY to HDL particles (green spheres) and desialylation of HDL by NanA modify the proteome and lipidome of HDL. In the arterial endothelium and intima the modified HDL particles (orange spheres) activate the complement system and macrophages and exhibit reduced ability to remove cholesterol (red arrow) from macrophages. HDL particles are further modified by oxidation. Macrophages are loaded with cholesterol from LDL particles (yellow spheres). The macrophages with large amounts of cholesterol become foam cells and undergo apoptosis, where after the cells will activate the complement system. Complement component C1q and C-reactive protein (CRP) have significant roles in complement-mediated clearance of apoptotic cells. In addition to HDL modification and cell lysis by PLY and NanA promote activation of platelets.
Schematic illustration of the putative mechanism how NanA could reduce complement regulation by factor H on the cells and sensitize cells for attack by complement and thereby lead to cell damage. In addition, NanA increases the susceptibility of cells to attack by pneumolysin (PLY) or other virulence factors.
Model for LukSF-receptor binding and the mechanism of LukSF-induced inflammation. (A). LukS (PDB ID: 1T5R) binds on hC5aR (structure based on angiotensin receptor data PDB ID: 4YAY, cyan dashed box) as a soluble monomer on the cell membrane. Each LukS monomer binds one hC5aR molecule via the receptor interacting residues R73, Y184, Y250, T244 (marked with blue dots) within a cluster of approximately 4-5 hC5aR homo-oligomers. Upon binding to hC5aR LukS exposes residues for LukF (PDB ID: 1LKF) binding (interface indiacted by dashed ellipse). In these tight clusters each LukF can bind to two LukS monomers via two interfaces. (B) Binding of LukF on LukS and formation of the octameric pore (PDB ID: 3B07) causes dissociation of the receptors from the complex because of leakage of the cell membrane and possibly also since the receptor binding region (marked with a circle) is buried between the monomers in the complex. (C) The detached hC5aR molecule can be reused by its ligands LukS or C5a anaphylatoxin (PDB ID: 1KJS). (D) Zoom out of (A-C), illustrating the putative mechanism of LukSF induced inflammation.
Schematic illustrating the putative mechanism of the effect of factor H-apoE interaction in reducing inflammation in atherosclerotic lesions. Binding of factor H on apoE containing HDL particles reduces plasma complement activation while elevated binding of apoE on monocytes/macrophages/foam cells via FH reduces local inflammation and cholesterol efflux.