Myeloid cells in experimental neuropathologies

The first innate immune cells, most importantly for this thesis macrophages, microglia and eosinophils, were described more than 100 years ago and only now do we begin to understand more about their development, functions and properties. So while elimination of pathogens through phagocytosis (macrophages/microglia) or degranulation (eosinophils) were long considered as their main functions, research during the last decades has made it clear that innate immune cells do much more than maintain homeostasis in an organism. Monocytes were considered the progenitors of all macrophages, migrating from the bloodstream into tissues in order to colonize them. A groundbreaking discovery changed our view of tissue macrophage development, proving that they are established during embryonic development and that they maintain themselves during homeostasis in tissues without input from circulating monocytes. Conversely, monocyte-derived macrophages primarily respond to pathogens or injury. Eosinophils were for a long time disregarded to have major functions in diseases other than allergies or parasitic infections. However, we now know that eosinophils not only play important roles in many diseases, including cancer, but also during homeostasis. In this thesis I describe how, in the event of significant loss of tissue macrophages, a tissue can be repopulated by rapid proliferation of resident cells in addition to infiltration from monocytes from the periphery. I have thus primarily studied microglia in the CNS niche under both homeostatic conditions and during disease states.

Our work identified TGF-β as a major signaling pathway involved in niche homeostasis and macrophage functional integration into the CNS. Loss of TGF-β signaling or an inability to respond to it led to deregulation of microglial function and infiltrating macrophage function, causing spontaneous initiation of a fatal motor disease characterized by demyelination and damage to neurons. We further established a role for eosinophils in a mouse model of Glioblastoma multiforme brain tumors, in which depletion of eosinophils led to significantly longer survival of tumor-bearing mice, which is in contrast to the current belief that macrophages are the most important and major infiltrating immune cell in most solid tumors. As a last approach, we used siRNA-loaded nanoparticles to reduce target gene expression of importance in tumor development in a mouse model of melanoma. Targeted delivery of therapeutic agents is one of the main obstacles in the treatment of cancer. Nanoparticles can be engineered to specifically target tumor cells or cells in the tumor vicinity and can be loaded with virtually any siRNA, without majorly affecting healthy cells and tissue. Using two delivery systems we demonstrated feasibility and efficacy of this approach.

In summary, in this thesis I highlight the importance of myeloid immune cells in health and disease and how targeting them could be of potential therapeutic interest in the future.

List of scientific papers

I. Harald Lund, Melanie Pieber, Roham Parsa, Jinming Han, David Grommisch, Ewoud Ewing, Lara Kular, Maria Needhamsen, Alexander Espinosa, Emma Nilsson, Anna K. Överby, Oleg Butovsky, Maja Jagodic, Xing-Mei Zhang, Robert A. Harris. Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nature Communications. 19;9(1):4845 (November 2018).
https://doi.org/10.1038/s41467-018-07295-7

II. Harald Lund, Melanie Pieber, Roham Parsa, David Grommisch, Ewoud Ewing Lara Kular, Maria Needhamsen, Sabrina Ruhrmann, André Ortlieb Guerreiro Cacais, Oleg Butovsky, Maja Jagodic, Xing-Mei Zhang, Robert A. Harris. Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling. Nature Immunology. 19(5), 1-7 (May 2018).
https://doi.org/10.1038/s41590-018-0091-5

III. Melanie Pieber, Roham Parsa, Harald Lund, Elizabeth A. Jacobsen, Robert A. Harris, Xing-Mei Zhang. Eosinophil depletion as a novel treatment in a mouse model of Glioblastoma multiforme. [Manuscript]

IV. Melanie Pieber, Keying Zhu, Vigneshkumar Rangasami, Oommen Podiyan Oommen, Myriam Aouadi, Robert A. Harris. Assessment of nanoparticle siRNA delivery in vitro and in vivo for the treatment of tumors in mouse models of melanoma and Glioblastoma multiforme. [Manuscript]