Deciphering and fine-tuning of myeloid cells in CNS demyelinating conditions

Demyelination in the central nervous system (CNS) is a characteristic of various neurological disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO), subacute combined degeneration (SCD), tabes dorsalis (syphilitic myelopathy), and more. Although the causes vary, CNS demyelination is often associated with a significant buildup of inflammatory activated myeloid cells, mainly consisting of CNS resident microglia and infiltrating monocyte-derived macrophages. On one hand, these myeloid cells can contribute to inflammation in the CNS and damage myelin, but on the other hand, they play a role in clearing myelin debris and releasing substances that facilitate myelin regeneration, a process known as remyelination. Therefore, it is crucial to determine the signals that control their specific functions and develop methods for regulating their activity.

In this thesis, we investigated the role of TGF-β signaling in regulating myeloid cell function. By using cell-specific targeting mouse tools, we discovered that when the CNS lacks microglia in a specific experimental setting, where peripheral monocytes can enter the CNS and repopulate the microglia pool by transforming into microglia-like macrophages, deleting the TGF-β receptor (TGFBR2) on monocytes prevents their entry into the CNS. Furthermore, when monocyte-derived macrophages are engrafted in the CNS, the depletion of TGFBR2 causes their abnormal activation and failure to adopt a microglia-like signature, leading to spontaneous demyelination in the spinal cord and a progressive, fatal motor disease. The loss of TGF- β signaling in microglia or monocyte-derived microglia-like cells preferentially targets myelin in the dorsal column of the spinal cord, and a subpopulation of microglia closely associated with myelin loss is identified in the dorsal column. We further characterized that this microglial TGF-β signaling loss-induced disease is more severe in female and older mice and uncovered potential molecular mechanisms underlying these gender and age differences in response to the loss of TGF-β signaling.

In addition to deciphering the mechanisms governing myeloid function, we also conducted translational studies aiming to provide therapeutic insights for demyelinating diseases. By using a drug screening tool and performing in vitro validation, as well as experiments in mouse models with CNS inflammation and ensuing demyelination, we confirmed the regulatory effect of topotecan, a topoisomerase 1 inhibitor, on myeloid cells, leading to improved disease outcome. We further developed a DNA nanostructure-based drug delivery system to encapsule topotecan and achieve specific targeting of TOP1 in myeloid cells, demonstrating that myeloid cell-specific inhibition of TOP1 could alleviate neuroinflammation. In the final study, within a non-inflammation-driven demyelinating context, we studied the role of TRPV1 activation in remyelination and revealed that the TRPV1 activator capsaicin could enhance microglial clearance of myelin debris following demyelination and promote remyelination.

My thesis work thus provides mechanistic understanding of how myeloid cells regulate myelin health and CNS homeostasis, while also providing regulatory strategies for fine-tuning these cells.

List of scientific papers

I. 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 A.O., Berglund R, Forteza M.J., Ketelhuth D.F.J., Butovsky O, Jagodic M, Zhang X-M#, Harris R.A.# Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling. Nature Immunology. (2018) 19, 1-7. #Equal contribution.
https://doi.org/10.1038/s41590-018-0091-5

II. Zhu K, Min J-H, Joshua V, Yun L, Pieber M, Suerth V, Sarlus H, Harris R.A.#, Lund H#. Impaired microglial TGF-β signaling induces severe demyelinating disease with regional-vulnerability and age/gender differences. #Equal contribution. [Manuscript]

III. Zhu K, Wang Y#, Sarlus H#, Geng K#, Nutma E, Sun J, Kung S-Y, Bay C, Han J, Min J-H, Benito-Cuesta I, Lund H, Amor S, Wang J, Zhang X-M, Kutter C, Guerreiro-Cacais A.O., Högberg B, Harris R.A. Myeloid cell-specific topoisomerase 1 inhibition using DNA origami mitigates neuroinflammation. EMBO Reports. (2022) 23: e54499. #Equal contribution.
https://doi.org/10.15252/embr.202154499

IV. Sun J#, Zhu K#, Wang Y#, Wang D, Zhang M, Sarlus H, Benito-Cuesta I, Zhao X, Zou Z, Zhong Q, Feng Y, Wang Y, Harris R.A., J Wang. Activation of TRPV1 receptor facilitates myelin repair following demyelination via the regulation of microglial function. Acta Pharmacologica Sinica. (2022) 0: 1–14. #Equal contribution.
https://doi.org/10.1038/s41401-022-01000-7