David Eikrem: Initiation and Regulation of Thromboinflammation

Abstract

Thromboinflammation is the description of an unwarranted immune response coinciding with thrombosis. Often leading to serious disorders like ST-elevated myocardial infarction (STEMI), stroke or complications associated with COVID-19. The factors instigating such disease pathogenesis revolve around the innate immune system. The innate immune components involved are platelet activation, the complement system, the coagulation cascade and the contact system. This thesis navigates the pathways involved by redefining their initiating mechanisms and sources on biological and material surfaces, presenting novel pathway crosstalk and avenues for future therapeutics. 

This thesis begins by revisiting the activation of the alternative pathway (AP) of complement through the relevance of C3(H2O). In paper I we present that the central complement component, C3 is activated on the surfaces of cells expressing distress patterns of altered self. This redefines the conventional idea of the alternative pathway simply being an amplifier of the classical and lectin pathways. Moving forth, paper II describes AP interactions with biomaterials. Now, at the forefront of medicine, applied in dialysis tubing and implants, we look into the toxic effects posed by nanoparticles leaking into the body. With C3 under the microscope, we identify a specific binding of Titanium dioxide nanoparticles to a region within the molecule responsible for AP convertase assembly.

This thesis proceeds then to investigate the contact system as in paper III, we pursue the natural physiological activator of Factor XII (FXII). Here, we present fibrin as an activator of the contact system initiating protein, FXII but also as a procoagulant surface. To deepen the understanding of innate immune pathway crosstalk, we aimed to link comeplement activity to coagulation by investigating the activity of the lectin pathway complement proteases, mannose associated serine proteases (MASPs) on FXII. In paper IV we discovered recombinant catalytic fragments of MASP-1 and MASP-2 enable activation of FXII, causing cleavage into beta FXIIa, a potent catalytic activator of the kallikrein-kinin system. 

In conclusion, we underline the importance surfaces have in our fundamental understanding of protein activation and inhibition and that moreover, crosstalk of plasma cascade systems unlock opportunity for therapeutic intervention.