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UNIVERSITY of CALIFORNIA Los Angeles Eosinophil Infiltration In UNIVERSITY OF CALIFORNIA Los Angeles Eosinophil Infiltration in Muscular Dystrophy: Key Characteristics and Contributions to Disease A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular, Cellular & Integrative Physiology by Albert Chi Sek 2020 © Copyright by Albert Chi Sek 2020 ABSTRACT OF THE DISSERTATION Eosinophil Infiltration in Muscular Dystrophy: Key Characteristics and Contributions to Disease By Albert Chi Sek Doctor of Philosophy in Molecular, Cellular & Integrative Physiology University of California, Los Angeles, 2020 Professor Tomas Ganz, Chair Duchenne Muscular Dystrophy (DMD) is a genetic disorder that affects 1 in 3,500 live male births. In DMD patients, inactivating mutations in the gene encoding dystrophin prevent expression of this critical cytoskeletal protein that is essential for myofiber integrity. Mutations in the gene encoding dystrophin have also been detected in muscular dystrophy (mdx) mice, which phenocopy the disease seen in DMD patients. As a result of dystrophin deficiency, the skeletal and cardiac muscles undergo severe degeneration accompanied by infiltration with inflammatory cells. Eosinophils are prominent among the leukocytes recruited to dystrophin-deficient skeletal muscle tissues, although their contributions to disease are incompletely understood. Eosinophils are capable of releasing cytotoxic mediators stored in cytoplasmic granules; as such, eosinophils have been viewed largely as mediators of tissue destruction. I began this work with an evaluation of the extent and impact of eosinophil infiltration on acute muscle damage in muscular dystrophy mice. Towards this end, I generated eosinophil-deficient (mdx.PHIL) and eosinophil-overabundant (mdx.IL5tg) strains of mdx mice. Despite the varied levels of eosinophil ii infiltration detected in skeletal muscle tissues, my studies revealed that there were remarkably similar levels of muscle damage in mdx, mdx.IL5tg and mdx.PHIL mice. This was evaluated by four key measures: histopathology scoring, distribution of myofiber sizes, proportion of centrally- nucleated myofibers and creatine kinase levels. To evaluate the functional characteristics of eosinophils recruited to dystrophin-deficient muscle tissue, I isolated eosinophils from the quadriceps muscles of mdx, IL5tg and mdx.IL5tg mice at 4 weeks of age, extracted RNA and performed RNA-sequencing. I identified 393 transcripts that were expressed at 5-fold higher levels in the eosinophils isolated from the muscle tissues of mdx mice when compared with those from IL5tg mice. Many of these transcripts encode tissue remodeling proteins (e.g., Ctss, Ctsk, Mmp19) as well as cell surface proteins (e.g., Cd14, Slc15a3, Trem2). By contrast, I identified 238 transcripts at 5-fold higher levels in eosinophils from the muscle tissues of IL5tg mice when compared with those from mdx mice. Many of these latter transcripts encode eosinophil-specific proteins (e.g., Ear1, Epx, Prg2) or proteins involved with cell cycle regulation. The findings that suggest differential expression of Trem2 are particularly intriguing, as TREM2 has been shown to promote the proliferation, activation and survival of myeloid cells in response to tissue damage. Hence, in order to evaluate the role of Trem2 in mediating eosinophil survival within dystrophin-deficient muscle tissues, we are currently generating mdx.Trem2-/- mice and will be in a position to evaluate eosinophil infiltration and survival in the muscle tissues of these mice. While generation of this strain is ongoing, I have determined that Trem2 is critical for full eosinophil development in both ex vivo and in vivo experimental studies. Taken together, these findings add to the growing body of evidence that suggests that eosinophils do not universally promote tissue destruction. In addition, findings presented in this dissertation highlight the unique features of eosinophils that may be uncovered through RNA- sequencing and analysis. Among the most intriguing findings, I established that Trem2 is critical iii for efficient eosinophil development. Further work will elucidate the regulation and functions of TREM2 expression in eosinophils. iv The dissertation of Albert Chi Sek is approved. John P. Chute Elizabeta Nemeth Eric Pearlman Helene F. Rosenberg James G. Tidball Tomas Ganz, Committee Chair University of California, Los Angeles 2020 v For Mom, Dad and Grace vi TABLE OF CONTENTS Abstract of the Dissertation ii List of tables and figures x Acknowledgements xiii Vita xvi Chapter 1: Introduction 1 Duchenne Muscular Dystrophy: A Severe Genetic Disorder 2 The mdx mouse model of Duchenne Muscular Dystrophy 3 Inflammation as a critical feature of muscular dystrophy pathogenesis 5 Eosinophil infiltration in dystrophin-deficient muscle tissue 6 Study of eosinophils in vivo and ex vivo: critical reagents and mouse models 7 This dissertation 8 References 14 Chapter 2: Detection and Isolation of Mouse Eosinophils from Muscle Tissue using Flow Cytometry 21 Preface 22 Abstract 23 Introduction 23 Methods and Results 25 Discussion 28 References 35 Chapter 3: Eosinophils Do Not Drive Acute Muscle Pathology in the mdx Mouse Model of Duchenne Muscular Dystrophy 38 Preface 39 vii Abstract 41 Introduction 41 Materials and Methods 42 Results 43 Discussion 47 References 48 Addendum 52 Chapter 4: Transcriptomic Profile of Eosinophils Recruited to Muscle Tissue of Dystrophin-deficient (mdx) mice 59 Preface 60 Abstract 61 Introduction 62 Materials and Methods 63 Results 65 Discussion 70 References 79 Chapter 5: Role of TREM2 in Modulating the Development and Characteristics of Eosinophils 82 Preface 83 Abstract 85 Introduction 85 Materials and Methods 87 Results 91 Discussion 96 References 106 viii Chapter 6: Conclusion 109 Eosinophilic infiltration does not always promote tissue destruction 110 Eosinophil infiltration in musculoskeletal disorders 111 RNA-sequencing enables functional characterization of eosinophils 113 Future Directions – Regulation and Function of TREM2 on Eosinophils 115 Concluding Remarks 117 References 118 ix LIST OF TABLES AND FIGURES Chapter 1 Figure 1.1 The mdx mouse model of Duchenne Muscular Dystrophy 11 Figure 1.2 Eosinophil infiltration and histopathology in quadriceps muscle tissue from mdx mice 12 Figure 1.3 Eosinophil characteristics: functional mediators and receptors 13 Chapter 2 Figure 2.1 Method for generating single cell suspensions from skeletal muscle 31 Table 2.1 Antibodies used for detection and isolation of eosinophils from skeletal muscle tissue 32 Figure 2.2 Flow cytometry strategy to identify eosinophils in skeletal muscle tissue 33 Figure 2.3 Morphological evaluation of SigF+CD11c+ and SigF+Gr1+ populations 34 Chapter 3 Figure 3.1 Histopathology and quantitative determination of eosinophils in the quadriceps muscle from wild-type, mdx, eosinophil-deficient PHIL, and mdx.PHIL mice 43 Figure 3.2 Histopathology and quantitative determination of eosinophils in the quadriceps muscle from IL-5 transgenic and mdx.IL5 transgenic mice 44 Figure 3.3 Quantitative indicators of muscle pathology 45 Figure 3.4 Eosinophil recruitment to muscle tissue 46 Figure 3.5 Cytokines detected in muscle tissue lysates 47 x Figure 3.S1 Additional images featuring lesions in quadriceps muscle from mdx mice 50 Figure 3.S2 Detection of centrally-located nuclei 51 Figure A1. Quantification of myofiber integrity and neutrophil infiltration in quadriceps muscle tissues from mice at 4 weeks of age 56 Figure A2. Histopathology and eosinophil infiltration in quadriceps muscle tissues from mice at 8 weeks of age 57 Figure A3. Histopathology and quantification of myofiber integrity in quadriceps muscle tissues from mice at 8 weeks of age 58 Chapter 4 Figure 4.1 Isolation of RNA from eosinophils from skeletal muscle tissues 74 Figure 4.2 Quality of RNA isolated from eosinophils from skeletal muscle tissues 75 Figure 4.3 Transcripts and gene ontology pathways that are differentially expressed in mdx vs IL5tg muscle eosinophils 76 Figure 4.4 Differentially expressed transcripts that are associated with tissue remodeling 77 Figure 4.5 Differentially expressed transcripts that encode cell surface proteins 78 Chapter 5 Figure 5.1 Differentiation of eosinophils ex vivo and detection of TREM2 100 Figure 5.2 Trem2 is required for efficient eosinophil expansion ex vivo 101 Figure 5.3 Trem2 gene-deletion alters eosinophil homeostasis in the bone marrow 102 Figure 5.4 Trem2 is not critical for eosinophil recruitment in response to a Th2-inflammatory stimulus 103 xi Figure 5.5 Generation of mdx.Trem2-/- mice 104 Figure 5.6 Variable expression of TREM2 on human peripheral blood eosinophils and correlation with donor BMI 105 xii ACKNOWLEDGEMENTS When I started graduate school in the fall of 2014, I had no idea of the non-linear, fast- moving and exponentially-rewarding journey that lay ahead. Through these experiences, I developed scientific and technical expertise, but also became a stronger writer, better presenter, and more critical thinker. I could not have imagined a better group of people to accompany and guide me along this remarkable period of personal and professional growth. First and foremost, I am immensely grateful for the guidance that my adviser Dr. Helene Rosenberg provided on a regular basis. Although I started this dissertation project well into my graduate training, Dr. Rosenberg encouraged me to pursue this project tenaciously and strategically. As a result of her spectacular mentorship, I was able to
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