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An Investigation of Beta-adrenergic Signaling Pathways among Peripheral Immune Cells in a Murine Model of Chronic Social Stress

Walsh, Catherine P (2023) An Investigation of Beta-adrenergic Signaling Pathways among Peripheral Immune Cells in a Murine Model of Chronic Social Stress. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Chronic social stress associates with an increase in peripheral pro-inflammatory markers and primed myeloid cells that can contribute to inflammatory health risk. Physiological pathways linking social stress to peripheral proinflammatory phenotypes remain unclear. Converging evidence shows chronic activation of the hypothalamic-pituitary(HPA)-axis in response to stress results in cellular resistance to anti-inflammatory effects of glucocorticoids. However, this does not fully account for stress-related proinflammatory phenotypes. Thus, it is possible that stress-induced activation of the sympathetic-adrenal-medullary(SAM)-axis may contribute. In this study, a well-established murine model of chronic social stress, repeated social defeat(RSD), was employed to examine whether stress induces changes in β-adrenergic receptor (β-AR) expression and related intracellular signaling within CD11b+ peripheral monocytes and granulocytes, which may contribute to proinflammatory phenotypes. Specifically, the possibility that stress induces a downregulation in β-AR surface expression and a shift from canonical β-AR-regulated intracellular signaling via CREB, to non-canonical signaling via MAPK was examined. As hypothesized, RSD associated with downregulation in β-AR surface expression and upregulation in pro-inflammatory gene transcription in CD11b+ cells isolated from the spleen and peripheral blood. There was also evidence for a “switch” in intracellular signaling, including a downregulation in β-AR canonical signaling and an upregulation in non-canonical β-AR signaling. The results were less clear when examining the cellular response to ex vivo isoproterenol stimulation, although initial evidence suggested stimulation with supraphysiologic levels of a β-adrenergic agonist may attenuate pro-inflammatory gene transcription via promotion of β-AR canonical signaling and attenuation in β-AR non-canonical signaling. Together, these results suggest a desensitization of peripheral monocytes and granulocytes from RSD mice to physiologic levels of adrenergic signaling, which may be adaptive in response to prolonged or repeated SAM-activation during chronic social stress. A molecular “switch” in β-adrenergic intracellular signaling may also preserve energy resources within the cell. However, the resultant promotion of pro-inflammatory gene transcription may pre-dispose the organism to inflammatory diseases of aging. Greater knowledge of cellular responses to chronic stress promotes understanding of proinflammatory phenotypes that associate with health risk and aids identification of novel targets for pre-emptive interventions that decrease risk for diseases with inflammatory pathophysiology known to accompany chronic social stress.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Walsh, Catherine Pcpw23@pitt.educpw230000-0002-8905-4544
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee CoChairMarsland, Anna
Committee CoChairSheridan,
Committee MemberManuck, Stephen
Committee MemberGianaros, Peter
Committee MemberBovbjerg, Dana
Committee MemberSved, Alan
Date: 26 January 2023
Date Type: Publication
Defense Date: 2 November 2022
Approval Date: 26 January 2023
Submission Date: 28 November 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 238
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Psychology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Chronic social stress, beta-adrenergic, inflammation, intracellular, health risk, murine
Date Deposited: 26 Jan 2023 15:13
Last Modified: 26 Jan 2023 15:13

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  • An Investigation of Beta-adrenergic Signaling Pathways among Peripheral Immune Cells in a Murine Model of Chronic Social Stress. (deposited 26 Jan 2023 15:13) [Currently Displayed]


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