The objective of this collaborative and synergistic program is to determine how interactions between immigrant neutrophils and macrophages and resident synovial fibroblasts lead to the formation of synovial pannus and joint destruction. Preliminary results have identified neutrophil and/or macrophage-derived protein/lipid mediators, and a synovial fibroblast adhesion molecule that regulate synovial inflammation in the K/BxN model of murine arthritis. Soluble mediators produced by immigrant inflammatory cells were found to target resident synovial fibroblasts to reprogram the synovial architecture. This program will determine how interactions between soluble mediators, their specific surface receptors, and regulatory proteins expressed by these lineages contribute to synovial inflammation. Project 1 will determine how interactions between CpG-containing oligodeoxyribonucleotides and TLR9 in macrophage/dendritic cells trigger an immune cascade that induces the expression of IFN-gamma and suppresses synovitis. Project 2 will determine how neutrophil-derived LTB4 targets synovial fibroblasts to promote synovitis. Project 3 will determine how post-transcriptional control mechanisms regulate the production of neutrophil-derived pro- and anti-inflammatory effector molecules that regulate synovitis. Project 4 will determine how cadherin 11, a synovial fibroblast adhesion molecule that regulates the architecture of synovial tissue, contributes to synovitis. An arthritis morphology core will provide uniform morphometric analysis of pathological samples and an arthritis genomics and bioinformatics core will facilitate the identification of novel genes that regulate synovial inflammation. The disease-focused mechanistic studies in this program promise both insight into the pathogenesis of inflammatory arthritis and identification of novel targets for therapeutic development. ?
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