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Lisong Yang
Biochemistry and Molecular Biology Program
B.S. 2005, University of Science and Technology of China

Thesis Advisor: Betsy Barnes, Ph.D.
Associate Professor
Department of Biochemistry and Molecular Biology

Friday, August 10, 2012
1:00 P.M., MSB-E609


The transcription factor interferon regulatory factor 5 (IRF5) has been identified as a human systemic lupus erythematosus (SLE) susceptibility gene by numerous joint linkage and genome-wide association studies. Although IRF5 expression is significantly elevated in primary blood cells of SLE patients, it is not yet known how IRF5 contributes to SLE pathogenesis. Recent data from mouse models of lupus indicate a critical role for IRF5 in the production of pathogenic autoantibodies and the expression of Th2 cytokines and type I interferon (IFN). In the current study, we examined in greater detail the mechanism(s) by which loss of Irf5 protects mice from pristane-induced lupus at earlier time-points of disease development. We demonstrate that Irf5 is required for Ly6C(hi) monocyte trafficking to the peritoneal cavity (PC) in response to pristane, which is believed to be one of the initial key events leading to lupus pathogenesis in this model. Results from chemotaxis assays using peritoneal lavage from pristane-injected Irf5+/+ mice as the chemoattractant support an intrinsic defect in Irf5-/- monocytes. We found the expression of chemokine receptors CXCR4 and CCR2 to be dysregulated on monocytes from Irf5-/- mice as compared to Irf5+/+ monocytes and Irf5-/- monocytes were less responsive to their respective ligands, CXCL12 and CCL2. Bone marrow reconstitution experiments further supported an instrinsic defect in Irf5-/- monocytes since Irf5+/+ monocytes were preferentially recruited to the PC in response to pristane. Further characterization of monocytes/macrophages (Mo/Mϕ) from the PC of pristane-injected bone marrow chimeric mice showed a decrease in Irf5-/- monocyte activation and an increase in the percentage of monocyte-derived dendritic cells (Mo-DCs). Together, these findings demonstrate an intrinsic role for IRF5 in the response of monocytes to pristane, and their recruitment to the primary site of inflammation that is thought to trigger lupus onset in this experimental model of SLE.

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