Arthritis continues to be a major source of morbidity worldwide. In most models of arthritis, neutrophils have been demonstrated to play a key role in the development of pathogenesis. The mechanism by which neutrophils mediate their effect, however, remains unknown. Lyme disease is caused by infection with the tick borne spirochete Borrelia burgdorferi (Bb). One major complication of this disease is the development of an inflammatory arthritis in most, but not all, patients untreated with antibiotics near the time of infection. Recently, using a mouse model of Lyme disease, we demonstrated a requirement for neutrophil recruitment into the joint tissue for the development of pathology. Joint homogenates from arthritis-susceptible mouse strains contained high levels of the chemoattractant KC, whereas joint homogenates from arthritis-resistant mouse strains did not. This suggested that polymorphisms in the initial host response to Bb infection by resident cells within the joint tissue led to the differential recruitment of neutrophils into the joints of resistant and susceptible mouse strains. Blocking the recruitment of neutrophils into the joint tissue in CXCR2 -/- mice resulted in a decrease in arthritis severity in both resistant and susceptible mouse strains. This application focuses specifically on the KC-mediated recruitment and activation of neutrophils in the ankle joint during Bb infection.
Specific Aim 1 will test the hypothesis that recruitment of neutrophils into the infected joint by KC is necessary and sufficient for development of Lyme arthritis. Treatment of Bfc-infected mice with polyclonal antibody to KC or rKC will test for the requirement or sufficiency of KC for arthritis development.
In Specific Aim 2 we will identify the cellular source of KC in joint tissue and test the hypothesis that sentinel cells within the joints of arthritis-resistant and -susceptible mice respond differently to Bb stimulation. Primary synovial fibroblasts from resistant and susceptible mouse strains will be co-cultured with Bb and the production of KC measured. Neutrophil modulation of the inflammatory response will also determined by the co-culture of neutrophils with synovial fibroblasts and measuring the production of KC in response to Bb stimulation. This proposal will define the role of KC in mediating the development of Lyme arthritis, but also addresses the broader issue of diversity within the innate immune response. As such these studies; may have important implications not only for Lyme disease, but for other inflammatory diseases as well.
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