Innate immunity in Staphylococcus aureus arthritis and sepsis

• Bacterial arthritis is a severe, rapidly progressing erosive disease with high morbidity and mortality. Staphylococcus aureus is the most common causative bacterium. Granulocytes together with cells from the monocyte/macrophage lineage, are the earliest leukocytes entering the synovial tissue in response to invading staphylococci. The recruitment of leukocytes from the vasculature and their extravasation into tissues is critical for a successful host response to infectious agent, but excessive acculmulation of leukocytes may also cause pathology. The role of granulocytes and macrophages in a model of haematogenously acquired S. aureus arthritis and sepsis was investigated. Phagocytosis by neutrophils recruited in the initial stage of S. aureus infection was found to be critical to the outcome of staphylococcal infection, since mice depleted of granulocytes prior to bacterial inoculation exhibited high mortality rate and severe arthritis. Cells of the monocytic lineage exerted a dual role in staphylococcal infection. Induced monocytopenia in S. aureus-infected mice resulted in (a) less severe arthritis, probably due to lower production of proinflammatory cytokines and (b) increased mortality, as a result of a diminished capacity to eliminate bacteria. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine promoting synthesis and maturation of phagocytic cells. GM-CSF treatment of S. aureus infected mice did not ameliorate arthritis. Our results indicate that excessive amount of GM-CSF is not beneficial in septic arthritis, possibly due to exaggerated in situ activation of phagocytic cells resulting in increased joint inflammation. The interactions between adhesion molecules on endothelial cells and their ligands on leukocytes are critical for their subsequent extravasation leading to joint inflammation. Blocking the adhesion molecules ICAM-1, and P-and L-selectins in infected mice resulted in delayed recruitment of leukocytes, leading to less severe and frequent arthritis. However, the same treatment gave rise to a less efficient phagocytosis and clearance of bacteria, resulting in higher mortality rates. This thesis provides an insight into how specific components of the innate immune system act in inflammatory diseases such as arthritis and how prophylactic and therapeutic treatments might be developed to reduce mortality and joint destruction in infected individuals.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

Nyckelord

Staphylococcus aureus

mice

sepsis

septic arthritis

neutrophils

monocytes/macrophages

GM-CSF

adhesion molecules

Publikations- och innehållstyp

vet (ämneskategori)

dok (ämneskategori)