Host modulation of excessive innate immune responses

Abstract: A fundamental role of the innate immune system is to elicit a proper response against both invading pathogens and tissue damage or danger signals. Although the innate immune system often is successful in eliminating danger, an excessive host-response can result in severe tissue injury. Factors that contribute to the elimination of the microbe are the same factors that cause tissue injury. Therefore, innate immune response has to be carefully balanced to avoid excessive inflammation with systemic consequences. The first part of this thesis is focused on molecular interactions between host-defense peptides and p33 (globular C1q receptor), a protein that can modulate cell injury. We show in vitro how recombinant p33 binds and neutralizes cytotoxic effects of the host-defense peptides human beta defensin 3 and LL-37. Moreover, treatment with p33 was also shown to modulate the sepsis-like pathogenesis caused by extracellular histones and rescue mice in a histone-induced shock model. Extracellular histones are released into tissue and circulation after cell necrosis or neutrophil extracellular trap formation. They are found in patients with severe inflammatory diseases and contribute to disease progression. However, for the first time, we have shown that extracellular histones contribute to resolving local inflammation. Low concentrations of extracellular histones contribute to innate immunity by inducing chemokine production and leukocyte recruitment which might be beneficial for the host. The final part of this thesis describes a novel defense mechanism of microvesicles against the gram-positive bacterium Streptococcus pyogenes. We show that procoagulant microvesicles are released after stimulation of pheripheral blood mononuclear cells with M1 protein from S. pyogenes. These microvesicles bind to the surface of bacteria, induce clotting and thereby prevent bacterial dissemination in vivo. In conclusion, this thesis describes new mechanisms involved in host defense as well as mechanisms involved in the modulation of excessive immune responses.