Genomic and functional analysis of monocyte-derived cells and microglia during experimental autoimmune encephalomyelitis
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Circulating Ly6C+ monocytes can replenish specific tissue-resident macrophages during adulthood and consequently can be interpreted as restricted macrophage precursor cells. Nevertheless, blood Ly6C+ monocytes are likely to present more than a transitional, undifferentiated cell population since they are characterized by own cellular functions that cannot be fulfilled by other monocyte subsets or macrophages. Importantly, tissue infiltration by Ly6C+ monocytes was described in almost all diseases and Ly6C+ monocytes seem to contribute to disease progression through tissue destruction, especially in autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS). However, recent technological advances like single cell RNA-sequencing (scRNA- seq) revealed that Ly6C+ monocytes are not homogenous, but instead represent a heterogeneous population with multiple origins. Therefore it is likely that different Ly6C+ monocyte subsets exist that are characterized by distinct cellular functions. A detailed knowledge about monocyte composition and their activation state during pathology possibly enables the development of therapeutic strategies, which either specifically block or deplete pathogenic cells, while increasing reparative properties in beneficial monocyte subsets. We therefore investigated in this Heisenberg Program the composition and heterogeneity of monocytes during EAE development. We were able to identify by scRNA-seq different Ly6C+ monocyte subsets that showed distinct transcriptomic profiles. These different gene signatures could be responsible for different functions of the monocytic subsets as suggested by gene enrichment analysis. However, part of the transcriptomic differences could also be explained by a sequential differentiation of monocytes within the inflamed central nervous system (CNS), while others might be the consequences of different origin. This assumption could be verified by cell transfer experiments, which revealed that classical Ly6C+ monocytes mainly differentiated into Nos2+ macrophages, while Cxcl10+ monocytes in the CNS derived from common myeloid precursor cells. By taking advantage of short-term cell depletion experiments, we were further able to show that Cxcl10+ monocytes disappeared from the CNS, while the presence of Nos2+ macrophages was not affected by this treatment regime. The absence of Cxcl10+ monocytes further reduced lymphocytic infiltration, which correlated with reduced disease severity. Accordingly, Cxcl10+ monocytes seem to be equipped with pathogenic activity that leads to direct and indirect tissue damage during autoimmune neuroinflammation. Taken together, our analysis revealed the presence of a previously unknown monocyte subset with a unique phenotype in the CNS of mice with EAE. It seems that these cells exhibit direct pathogenic function with additional influences on the recruitment of other immune cells such as lymphocytes. Since Cxcl10+ monocytes were also reported in other inflammatory conditions, specific targeting of these cells might represent a promising strategy for therapeutic intervention in MS and other pathologies.
Publications
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(2017): Genomic Characterization of Murine Monocytes Reveals C/EBPβ Transcription Factor Dependence of Ly6C- Cells. Immunity. 46(5):849-862.e7
Mildner A, Schönheit J, Giladi A, David E, Lara-Astiaso D, Lorenzo-Vivas E, Paul F, Chappell-Maor L, Priller J, Leutz A, Amit I, Jung S
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(2018): Developmental and Functional Heterogeneity of Monocytes. Immunity. 16;49(4):595-613
Guilliams M, Mildner A, Yona S
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(2018): Good things come in threes. Sci Immunol. 3(30):eaav5545
Yona S, Mildner A
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(2019): Mapping the lung. Science. 363(6432):1154-1155
Mildner A, Yona S
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(2020): C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells. Cell Stem Cell. 26(5):793
de Laval B, Maurizio J, Kandalla PK, Brisou G, Simonnet L, Huber C, Gimenez G, Matcovitch-Natan O, Reinhardt S, David E, Mildner A, Leutz A, Nadel B, Bordi C, Amit I, Sarrazin S, Sieweke MH
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(2020): Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation. Nat Immunol. 21(5):525-534
Giladi A, Wagner LK, Li H, Dörr D, Medaglia C, Paul F, Shemer A, Jung S, Yona S, Mack M, Leutz A, Amit I, Mildner A
