Regulation of microglia and monocyte function by the cytokine TGF-beta

It has been almost a century since Pío del Río-Hortega described the microglial cell, proposing it to be primarily occupied with phagocytosis of waste products. While this makes up one of its functions, we know today that microglia participate in numerous tasks and can interact with and regulate all other cell types of the brain. Given this knowledge, it is perhaps not surprising that microglia dysfunction has been implicated in a wide range of neurological disorders, including diseases of neuroinflammatory (multiple sclerosis), neurodevelopmental (schizophrenia) and neurodegenerative (amyotrophic lateral sclerosis and Alzheimer’s disease) character.

Monocytes are produced in the bone marrow and are released into the bloodstream from where they can infiltrate virtually any tissue, either as a homeostatic process to replace the local macrophage pool, or as an inflammatory response to tissue damage. Monocytes can engraft the central nervous system under various conditions and are historically recognized as the main drivers of the demyelinating process that clinically manifests as multiple sclerosis. However, given the right signals, monocytes can also integrate into the neural network and become permanent residents of the brain. The work presented in this thesis explores how these distinct processes are regulated by the cytokine TGF-β.

Using conditional gene targeting approaches we investigated the role of TGF-β signaling in monocytes during autoimmune neuroinflammation as well as during homeostatic replacement of microglia after experimental depletion. We demonstrate that, when autoimmune paralysis is established, TGF-β suppresses monocyte effector functions including pro-inflammatory cytokine production and oxidative damage, which initiates remission of disease. Subsequently, in a setting of microglia loss, monocytes required TGF-β to colonize the microglial niche and to maintain microglia-like phenotype and function. Abrogation of TGF-β signaling in monocytederived microglial replacements resulted in the spontaneous initiation of demyelination and neuronal damage that clinically presented as a progressive and fatal motor disease.

In summary, our studies provide novel mechanisms by which TGF-β regulates brain homeostasis, which are likely deregulated during disease and that could be pharmacologically targeted.

List of scientific papers

I. Parsa R, Lund H, Tosevski I, Zhang XM, Malipiero U, Beckervordersandforth J, Merkler D, Prinz M, Gyllenberg A, James T, Warnecke A, Hillert J, Alfredsson L, Kockum I, Olsson T, Fontana A, Suter T and Harris RA. TGFβ regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte-derived dendritic cells. Glia. 64(11), 1925-1937 (2016).
https://doi.org/10.1002/glia.23033

II. Lund H, Pieber M, Parsa R, Han J, Grommisch D, Ewing E, Kular L, Needhamsen M, Butovsky O, Jagodic M, Zhang XM, Harris RA. Competitive repopulation of an empty microglial niche gives rise to functionally distinct subsets of microglia-like cells. [Manuscript]

III. Lund H, Pieber M, Parsa R, Grommisch D, Ewing E, Kular L, Han J, Zhu K, Nijssen J, Hedlund E, Needhamsen M, Ruhrmann S, Guerreiro-Cacais AO, Berglund R, Forteza MJ, Ketelhuth DFJ, Butovsky O, Jagodic M, Zhang XM, Harris RA. Fatal demyelinating disease is induced by monocytederived macrophages in the absence of TGF-β signaling. Nature Immunology. 19(5), 1-7 (2018).
https://doi.org/10.1038/s41590-018-0091-5

IV. Lund H, Zhu K, Pieber M, Ohshima M, Blomgren K, Zhang XM, Harris RA. Long-term effects of microglial depletion on tau pathology and spatial memory. [Manuscript]