NOREPINEPHRINE REGULATION OF INFLAMMATORY RESPONSES DURING MONOCYTE ACTIVATION AND DIFFERENTIATION AND DURING ACUTE STRESS IN PATIENTS WITH MAJOR DEPRESSION Público

Abstract

Activation of the sympathetic nervous system and release of catecholamines, such as norepinephrine (NE), regulate inflammation through interactions with the innate immune system. Although crosstalk between these two systems is clear, the role of NE in mediating inflammatory responses is less clear, with evidence of both pro- and anti-inflammatory effects. To further understand these paradoxical effects of NE, we examined the impact of cellular activation and differentiation on inflammatory cytokine production after NE administration to a human monocyte cell line. Using lipopolysaccharide (LPS) to induce cellular activation, we showed that NE inhibits interleukin (IL)-6 protein release from the monocytic form of the cell, when administered before LPS. However, treating the cells with NE after LPS-induced activation led to a decrease in NE's inhibitory effects. NE inhibition of LPS-induced IL-6 was shown to be mediated by the beta 2-adrenergic receptor (B2-AR) as well as cAMP. Interestingly, the decreased sensitivity to NE following monocyte activation by LPS was found to be mediated by a PKA-dependent decrease in B2-AR mRNA. Indeed, blocking PKA reversed B2-AR mRNA downregulation and restored cell sensitivity to NE. Differentiation of cells from the monocyte state to the macrophage state also resulted in decreased NE sensitivity, likely a result of increased mRNA expression of beta arrestin-2 (BARR-2), which can lead to B2-AR desensitization. Finally, LPS-induced activation of cells in the macrophage state completely abolished NE's anti-inflammatory effects, in association with both decreased B2-AR mRNA as well as decreased mRNA for BARR-2, which can inhibit inflammatory responses. To study the impact of NE on inflammation in vivo, we examined stress-induced NE and IL-6 release in patients with major depression versus healthy controls. We found that patients with depression exhibited reduced sensitivity to NE, as depressed patients with high NE responses to stress exhibited the highest stress-induced IL-6 responses. Taken together, these studies indicate that NE primarily functions to inhibit inflammation. However, the extent of NE's anti-inflammatory action is dynamic and depends on the physiological state of the cell. Dysregulation of NE's anti-inflammatory effects may contribute to pathology in diseases involving inflammation, such as depression.

Table of Contents

TABLE OF CONTENTS

Page
Chapter One - Introduction: Interplay Between Inflammation and the
Sympathetic Nervous System: Role of Adrenergic Receptors 1
I. Immune-nervous system interactions: A historical perspective
on catecholaminergic immunomodulation 2
II. Innate immune system 4
III. Innate immunity and stress 17
IV. The sympathetic nervous system and inflammation 22
V. Summary 58
Chapter Two - Beta-2 adrenergic receptor regulation of inflammatory
responses in resting and activated monocytes and differentiated
macrophages 67
I. Introduction 68
II. Methods 71
III. Results 74
IV. Discussion 83
Chapter Three - Differential norepinephrine regulation of stress-induced
inflammatory responses in subjects with major depression versus healthy
controls 111
I. Introduction 112
II. Methods 115
III. Results 118
IV. Discussion 119
Chapter Four - Conclusions and future directions 130
I. Summary of results 131
II. Limitations and future directions: In vitro studies 134
III. Limitations and future directions: In vitro studies 141
IV. Concluding remarks 146
References 151

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience Health Sciences, Immunology
Palabra Clave	depression macrophage interleukin-6 norepinephrine monocyte
Committee Chair / Thesis Advisor	Miller, Andrew H, Emory University
Committee Members	Hall, Randy A, Emory University Pace, Thaddeus, Emory University Heim, Christine Marcelle, Emory University Weiss, Jay M, Emory University

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