Sunday, November 24, 2024
11/24/2024
Our new preliminary data indicate that ErbB3 signaling is essential for the integration of early inflammatory response with adaptive immunosuppression, thus preventing the activation of cardiac lymphocytes and protecting the heart against secondary immune cell-mediated tissue damage. We found that ErbB3 upregulates the expression of PD-L1 on myeloid cells in response to their stimulation with inflammatory factors. Myocardial tissue lymphocytes express high levels of PD-1 that inhibit the activation of T cells upon binding to PD-L1 on myeloid cells. Reduced level of PD-L1 expression in mice with disrupted ErbB3 signaling is associated with activation of cytotoxic lymphocytes and myocardial dysfunction in a mouse model of LPS- driven inflammation. We also found that ErbB3 promotes up-regulation of PD-L1 after ischemia-reperfusion (I/R) cardiac injury. To better understand the role of ErbB3 in the regulation of the PD-L1/ PD-1 axis and myocardial protection, we generated novel mouse models with ablation and overexpression of ErbB in myeloid cells and subsets of myeloid cells, including macrophages, dendritic cells, and Ly6Clow monocytes. In specific aim 1, we will determine the role of ErbB3 in the regulation of the myocardial PD-L1/PD-1 axis and immunosuppression during the acute inflammatory response using loss-of-function and gain-of-function mouse models. In specific aim 2, we will test the hypothesis that ErbB3 downstream signaling promotes synthesis and prevents degradation of PD-L1 in myeloid cells. In specific aim 3, we will determine the role of lymphocyte activation and Ly6Clow monocytes in the promotion of fibrosis in remote myocardial areas in mice with disrupted ErbB3 signaling in myeloid cells.
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