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Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction Through Disruption of Lxrα Signaling in Macrophages

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Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction Through Disruption of Lxrα Signaling in Macrophages Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction Through Disruption of LXRα Signaling in Macrophages A dissertation to be submitted to the Graduate School of the University of Cincinnati In partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in the Department of Pharmacology and Systems Physiology, College of Medicine, 2020 By: Yutian Li B.S. in Pharmaceutical Science from The Ohio State University, 2012 M.S. in Molecular, Cellular and Biochemical Pharmacology from University of Cincinnati, 2014 Committee Members: Guo-Chang Fan, Ph.D (Chair) David Hui, Ph.D Terence Kirley, Ph.D Diego Perez-Tilve, Ph.D Jack Rubinstein, MD David Wieczorek, Ph.D Abstract Acute and chronic inflammation are reflected by systemically greater abundance of proinflammatory cytokines and increased infiltration and activation of immune cells in various tissues. In particular, cardiac dysfunction is a common ailment associated with both acute and chronic inflammatory states. As a fundamental component of innate immunity, macrophages play critical roles in both initiating and resolving inflammation in the heart. In fact, macrophages are prominent cells that drive septic cardiomyopathy in animal models; and human monocytes/macrophages secrete more inflammatory cytokines in type 2 diabetic patients and positively correlate with atherosclerosis severity. Secreted and transmembrane protein 1 (Sectm1, also referred to as K12) is a type 1 transmembrane protein. The knowledge of Sectm1 function in human diseases is currently limited to its role as an alternative CD7 ligand to stimulate T cell proliferation. Whether Sectm1 plays a role in normal macrophage biology and inflammatory diseases has never been investigated. In this dissertation, we observed that mRNA levels of Sectm1a (mouse homolog of human Sectm1) was significantly increased in early time points (peak at 6 h), but reduced at later time points in LPS-treated bone marrow-derived macrophages (BMDMs) and spleen of wild-type (WT) mice injected with LPS. To determine the role of Sectm1a in macrophage activation and inflammation-induced cardiac injury, we generated a Sectm1a-knockout (KO) mouse model in which LPS-induced cardiac injury and mortality were greatly augmented. Further analysis revealed that inflammatory macrophages in hearts of KO-LPS mice was greatly accumulated, compared to WT-LPS controls. In accordance to the activated macrophage phenotype, lack of Sectm1a dramatically increased the production of inflammatory cytokines (TNFα, IL-6, and IL- i 1β) and MCP-1 levels both in vitro (BMDMs) and in vivo (in serum and myocardium) after LPS challenge. Moreover, we detected significantly lower levels of proinflammatory cytokines when overexpressing Sectm1a in BMDMs, but not in cardiomyocytes. Most importantly, transplantation of Sectm1a-KO bone marrow cells into WT mice resulted in increased accumulation of inflammatory macrophages in the heart and aggravated cardiac dysfunction upon LPS challenge. These data suggest that ablation of Sectm1a induces cardiac dysfunction through activation of immune responses mediated by macrophages. Furthermore, RNA-sequencing results, along with bioinformatics analyses showed that many of the LXRɑ target genes are significantly downregulated in Sectm1a KO BMDMs. Furthermore, ablation of sectm1a hinders the nuclear translocation of LXRα in response to GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines. In addition, administration of GW3965 fails to rescue cardiac function in KO mice upon LPS injection. Notably, coimmuno- precipitation (Co-IP) results suggest potential physical interaction between Sectm1a and LXRα. Lastly, using chronic inflammation model induced by high-fat diet (HFD, 18-24 week) feeding, we also observed that infiltration of inflammatory monocytes/ macrophages in KO-hearts was dramatically increased, leading to aggravated cardiac dysfunction, compared to WT-HFD controls. In summary, this study defines a novel function of Sectm1a in macrophage biology, and identifies a new cellular mechanism for Sectm1a in the regulation of macrophage activation via LXRα signaling cascade, and its relationship to inflammation-induced cardiac injury. ii (Blank Page) iii Acknowledgement Throughout the entire journey towards earning my Ph.D. degree, I have been very fortunate to meet different people and make many friends, who have played significant role in my professional and personal development. Their support and encouragement are absolutely indispensable, making this endeavor much more enjoyable and fruitful than it could possibly be, and for this I will always be grateful. First, I want to express my sincere gratitude to my thesis advisor, Dr. Guo-Chang Fan, for providing me a strong platform and countless guidance along my path to becoming an independent scientist. Being a great mentor as he is, Dr. Fan has always been extremely supportive and inspiring, his passion to science and rigorous work ethic had motivated me to maximize my potential on the daily basis. He is attentive to details and has regularly trained me on reviewing others’ publications and writing protocols/fellowship applications. All these had significant improved my critical thinking, writing, and presentation skills, and has been invaluable tools to my professional and personal development that will benefit me for the rest of my life. Apart from being an exemplary scientist, Dr. Fan is also a great host and organizer for many fun events that I enjoyed during the past few years: celebrating birthdays and holidays, or when manuscripts had been accepted for publication or new funding was awarded. Furthermore, I would like to acknowledge my committee members, Drs. David Hui, Terence Kirley, Jack Rubinstein, Diego Perez-Tilve, and David Wieczorek, for their constructive and idea-inspiring criticism, which kept me moving forward with my projects and ensured the timely completion of this dissertation. I am very thankful that they were always encouraging me and available to discuss my projects. iv Next, I’d also like to extend my appreciation to many great collaborators. First, I am greatly appreciative of the mentoring and training on metabolic studies received from Dr. Hui’s lab when I did my lab rotation in his lab and throughout my graduate study; particularly, I’d like to thank Dr. Allyson Hamlin, David Kuhel, James Cash, and Joshua Basford, who taught me all the basic techniques commonly used in metabolic studies and answered endless question that I had. In addition, I would like to thank Jenna Holland and Emily Yates, in Dr. Diego Perez- Tilve’s lab, who helped me with the project of Hsp20’s role in regulation of adipocyte function, which broadly expand my knowledge in lipid studies. Moreover, I would like to extend my gratitude to Dr. Rubinstein, and his lab members, Mr. Nathan Robins and Dr. Sheryl Koch, for their time and effort in performing and analyzing echocardiography as well as explaining the technique for me to understand the project better. Also I want to thank Dr. Yigang Wang for allowing me to use some of their equipment; particularly, I’d like to thank Wei Huang for assisting me with some of the echocardiography and Co-IP experiments. I’d also like to acknowledge many great people in the Department of Pharmacology and Systems Physiology. I am very appreciative to Drs. John Maggio, Abdul Matlib, and Robert Rapoport for their guidance and mentorship since the beginning of the Master Program and throughout my graduate study. I also like to express my gratitude to Nancy Thyberg and Jeannie Cummins, who are extremely supportive in all matters and keep me in track to finish things in time, they are the first go-to person whenever I have any question, and they will always be ready to help. I’m also very thankful to my classmates and fellow graduate students, Kobina Essandoh, George Gardner, Fawzi Alogaili, Jiuzhou Huo, for their collaboration and friendship for the past several years. v I am fortunate to have encountered many great people in the Fan lab. Particularly, I want to thank Dr. Xiaohong Wang for her mentorship and endless support throughout my graduate study, making it more enjoyable. I also owe my sincere gratitude to the past and present members, Drs. Liwang Yang, Dongze Qin, Haitao Gu, Jiangtong Peng, Shan Deng, Xingjiang Mu, Peng Wang, Hongyan Zhao, Lu Wang, and Shunan Cui for their assistance and friendship. I am honored to be awarded with the University Research Council Award, Albert J. Ryan Fellowship, and the American Heart Association Pre-Doctoral Fellowship, which all provided me valuable resources and allowed me to network with fellow students and former awardees at annual symposiums. In addition, I’d like to thank Drs. Hong-Sheng Wang, Yigang Wang, and David Wieczorek for their full support on my AHA Pre-Doc Fellowship application. Lastly, I would like to thank my parents for their unconditional love and support, I’m thankful for their patience, encouragement and guidance throughout my life, and I’m forever grateful for their sacrifice for me to pursue my career. Next, I want to thank my wife, Yuqiu, for her overwhelming support and being the best cook in the world, thank you for believing in me and talking care of my life, I’m very blessed to have you in my life. vi (Blank page) vii Table of Contents Abstract i Acknowledgement iv Table of Contents 1 List of Abbreviations 4 List of Figures and Tables 8 Chapter I: Introduction 11 Section 1: Introduction of Inflammation-Associated Cardiac Dysfunction 11 I.1.A. Overview of Acute and Chronic Inflammation 12 I.1.B. Effects of Inflammation on Cardiac Function 16 I.1.C. Functional Roles of Macrophages in the Heart 21 Section 2: Human Secreted and Transmembrane Protein 1 (Sectm1) and 23 Its Mouse Homologs Sectm1a/Sectm1b I.2.A. Discovery, Structure and Expression of Sectm1 23 I.2.B. Functional Roles of Sectm1 in Immunity 25 I.2.C. Mouse Homologs Sectm1a and Sectm1b 26 Section 3: Role of Liver X Receptor in Macrophages 28 I.3.A.
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