Role of Hematopoietic Stem Progenitor Cells in Stress-Induced Apoptosis

East Tennessee State University, Johnson City TN

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Abstract

? DESCRIPTION (provided by applicant): The overall goal of these studies is to define the mechanism(s) underlying hematopoietic stem-progenitor cells (HSPCs) mediated immune suppression during stress. Stress has dramatic impacts on the immune system and consequently contributes to the onset and progression of a variety of diseases, including immune disorders, infections, and cancer. However, the mechanisms by which stress affects the immune system remain to be elucidated. Recent evidence from us and others has shown that HSPCs play an important role in the regulation of immune and inflammatory responses. We utilize a mouse model of restraint stress, which has been widely used, including in our laboratory and others, to study the effects of stress on immune responses. Using this model we discovered that HSPCs prevent restraint stress-induced splenocyte apoptosis. We found that IL-4 is essential for the protective effects of HSPCs on splenocyte reduction induced by stress. To the best of our knowledge, this is a new and novel role for HSPCs in the pathogenesis of stress-induced immune responses. However, the mechanisms by which HSPCs regulate stress-induced immune suppression are not known. At present, we do not understand the role of HSPCs in immune suppression induced by stress, nor do we understand the effect of HSPC-mediated IL-4 signaling on lymphocyte apoptosis during stress. Based on our novel findings, we hypothesize that HSPCs prevent stress-induced immune suppression by modulating IL-4 signaling. We propose the following two aims to test this hypothesis. Aim 1 will define the role of HSPCs in stress-induced immune suppression. We hypothesize that HSPCs protect from immune suppression induced by stress. To text this hypothesis, wild type mice will be administered HSPCs or heat-killed HSPCs as vehicle, and then subjected to restraint stress for different time periods. We will determine the effect of HSPCs on lymphocyte apoptosis and immune responses following stress. Aim 2 will investigate the effect of HSPCs on IL-4-mediated apoptotic signaling following stress. Our hypothesis is that HSPCs prevent stress-induced lymphocyte apoptosis though IL-4-mediated signaling. We will administer HSPCs and IL-4 neutralizing antibody, and then subject mice to restraint stress for different time periods. The effect of HSPC-mediated IL-4 signaling on lymphocyte apoptosis will be evaluated. To further define the mechanism by which IL-4-mediated signaling contributes to the protective effect of HSPCs on stress-induced lymphocyte apoptosis, we will utilize IL-4 knockout mice to verify the role of IL-4 in this process. Our studies should delineate the mechanisms underlying HSPC-mediated signaling in immune suppression and provide novel information for the development of effective countermeasures against stress.