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Tlr4 Neuroinflammatory Signaling And TLR4 NEUROINFLAMMATORY SIGNALING AND THE ANTI-INFLAMMATORY EFFECTS OF FENTANYL AND MORPHINE IN CHME-5 MICROGLIAL CELLS By LEANDRA K. FIGUEROA-HALL Bachelor of Science in Biology University of the Virgin Islands St. Thomas, USVI 2008 Master of Science University of Maryland, School of Medicine Baltimore, MD 2011 Submitted to the Faculty of the Graduate College of the Oklahoma State University in partial fulfillment of the requirements for the Degree of DOCTOR OF PHILOSOPHY July 2017 TLR4 NEUROINFLAMMATORY SIGNALING AND THE ANTI-INFLAMMATORY EFFECTS OF FENTANYL AND MORPHINE IN CHME-5 MICROGLIAL CELLS Dissertation Approved: Dr. Randall L. Davis Dissertation Adviser Dr. Craig W. Stevens Dr. J. Thomas Curtis Dr. Kent Teague Dr. Robert W. Allen ii ACKNOWLEDGEMENTS First and foremost, I would like to thank God for giving me the strength and tenacity to achieve this lifelong goal. Without Him nothing is possible. Secondly, I would like to dedicate my dissertation to my grandmother, Petra Melendez (Mama), who passed last year July. I would always call Mama on my drive to and from school, and she would ask, “going home so late”, “you going in on the weekend, or “when are you finishing?” That always made me laugh. I know she is looking down and is very proud of what I have accomplished. I would also like to thank my husband, Keith, for supporting me throughout all of these years. Thank you for doing the dishes, laundry, and taking care of Christian when I had to be at school late nights or on the weekends. Just know that this is not only my success, but also ours. Love you to the moon and back! A special thanks to my parents, Juan and Catherine Figueroa, and my brother, Juan Figueroa-Serville, and his family, for always believing in me and supporting me throughout all these years. I love you very much. And finally, my acknowledgements would not be complete without thanking my Oklahoma State University family. Thank you Dr. Davis, for your dedication and advice throughout my time in your lab. Because of you I have matured as a critical thinker and scientist. I will always be proud to say that I received my Ph.D. under your mentorship. A special thank you to all of my committee members for your support and guidance: Dr. Craig W. Stevens, Dr. J Thomas Curtis, Dr. Robert W. Allen, and Dr. Kent Teague. Thank you to Michael Anderson, who collaborated with the immunocytochemistry studies. And last but not least, to Joni, Kelly, and Daniel, thank you for putting up with me during all these years. If it were not for you I probably would not have had such an easy breezy time at OSU! Love you guys! iii Acknowledgements reflect the views of the author and are not endorsed by committee members or Oklahoma State University. Name: LEANDRA K. FIGUEROA-HALL Date of Degree: JULY, 2017 Title of Study: TLR4 NEUROINFLAMMATORY SIGNALING AND THE ANTI- INFLAMMATORY EFFECTS OF FENTANYL AND MORPHINE IN CHME-5 MICROGLIAL CELLS Major Field: BIOMEDICAL SCIENCES Abstract: Microglia are instrumental in neuroinflammation, which is a key factor in neuronal damage in many neurological disorders. Pro-inflammatory mediators activate these cells, including bacterial lipopolysaccharide (LPS) that signals through toll-like receptor 4 (TLR4). In the field of neuroinflammation, identifying the specific effects of pharmacological agents and other factors on microglia is often problematic given the difficulty and expense in obtaining and culturing primary microglia. Thus, immortalized microglial cell lines are very useful. Therefore, characterization of LPS-induced TLR4 signaling in the CHME-5 microglial cell line was expected to be of value as an experimental model of inflammatory signaling in the central nervous system (CNS). Inflammatory signaling in response to Escherichia coli LPS induced IκBα and NF-κB p65 activation, NF-κB p65 binding activity, and TNFα gene expression. We confirmed the maintenance of microglial phenotype as seen with increased CD68 expression and the absence of GFAP-immunoreactivity. TLR4 expression was significantly increased after LPS treatment. Another family of receptors expressed in the CNS is the opioid receptors, which are guanine protein coupled receptors (GPCRs) and mediate their effects with the binding of opioids. Most notably, the mu opioid receptor (MOR) is expressed in many organ systems and binds opioid agonists, morphine and fentanyl, and antagonists, naloxone and naltrexone. Research shows that opioids modulate immune function, and therefore, our goal was to determine the effects of fentanyl and morphine on LPS-induced TLR4 signaling in CHME-5 cells. Co-treatment with LPS and fentanyl revealed a significant decrease in IκBα activation and NF-κB p65 binding activity, while morphine only decreased IκBα activation. Conversely, no differences in LPS-induced TLR4 or MyD88 expression were seen with co-treatment of fentanyl or morphine. Finally, treatment with naltrexone following LPS and fentanyl co-treatment did not reverse the opioid-mediated effect on NF-κB p65 binding activity. We have shown that CHME-5 microglial cell attributes are conserved, which makes these cells a beneficial tool for studying microglial inflammatory signaling. Additionally, results demonstrate that fentanyl, and to a lesser extent morphine, display anti-inflammatory effects through down-regulation of IκBα activation and NF-κB p65 binding activity, which may be instrumental during treatment of CNS-localized insults or neurodegeneration. iv TABLE OF CONTENTS CHAPTER ONE: TLR4-NEUROINFLAMMATORY SIGNALING IN CHME-5 MICROGLIAL CELLS ...................................................................................................... 1 LITERATURE REVIEW ................................................................................................... 2 TOLL-LIKE RECEPTORS ........................................................................................................................................ 2 GRAM-NEGATIVE LPS .......................................................................................................................................... 4 TLR4 RECOGNIZES GRAM-NEGATIVE LPS .................................................................................................... 4 MYD88-DEPENDENT SIGNALING ...................................................................................................................... 5 TRIF-DEPENDENT SIGNALING ........................................................................................................................... 6 TOLL-LIKE RECEPTORS EXPRESSED IN THE CENTRAL NERVOUS SYSTEM ......................................... 7 NEUROINFLAMMATION IN THE CENTRAL NERVOUS SYSTEM ................................................................. 8 NEURODEGENERATION ......................................................................................................................................... 9 IDENTIFICATION OF MICROGLIA ..................................................................................................................... 12 ORIGIN AND DEVELOPMENT ............................................................................................................................. 13 MICROGLIAL FUNCTION ..................................................................................................................................... 15 NEUROPROTECTIVE VS. NEUROTOXIC .......................................................................................................... 17 SURFACE ANTIGENS/RECEPTORS ................................................................................................................... 17 CYTOKINES/CHEMOKINES ................................................................................................................................. 18 EXPERIMENTAL TOOL FOR THE STUDY OF MICROGLIA ............................................................................ 18 PRIMARY CELLS .................................................................................................................................................... 19 CELL LINES ............................................................................................................................................................. 19 METHODOLOGY ........................................................................................................... 24 CELL CULTURE ..................................................................................................................................................... 24 LPS TREATMENT .................................................................................................................................................. 24 v MTT ASSAY ............................................................................................................................................................ 24 PROTEIN EXTRACTION ........................................................................................................................................ 25 PROTEIN ASSAY ..................................................................................................................................................... 26 IMMUNOBLOT ANALYSIS .................................................................................................................................... 26 RNA EXTRACTION ............................................................................................................................................... 28 RNA INTEGRITY ..................................................................................................................................................
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