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Published on: April 13, 2017
Peripherally derived myeloid cells induce disease-dependent phenotypic changes in microglia
Estrid Thougaard1,2, Brianna Carney3, Agnieszka Wlodarczyk1,2
1Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Abstract:
In central nervous system (CNS) injury and disease, peripherally derived myeloid cells infiltrate the CNS parenchyma and interact with resident cells, propagating the neuroinflammatory response. Because peripheral myeloid populations differ profoundly depending on the type and phase of injury, their crosstalk with CNS resident cells, particularly microglia, will lead to different functional outcomes. Thus, understanding how peripheral myeloid cells affect the phenotype and function of microglia in different disease conditions and phases may lead to a better understanding of disease-specific targetable pathways for neuroprotection and neurorepair. To this end, we set out to develop an in vitro system to investigate the communication between peripheral myeloid cells and microglia, with the goal of uncovering potential differences due to disease type and timing. We isolated peripheral myeloid cells from mice undergoing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, or acute cerebral ischemia by permanent middle cerebral artery occlusion (pMCAO) at different times after disease and probed their ability to change the phenotype of primary microglia isolated from the brain of adult mice. We identified changes not only dependent on the disease model, but also on the timepoint after disease onset from which the myeloid cells were isolated. Peripheral myeloid cells from acute EAE induced morphological changes in microglia, followed by increases in expression of genes involved in inflammatory signaling. Conversely, it was the peripheral myeloid cells from the chronic phase of pMCAO that induced gene expression changes in genes involved in inflammatory signaling and phagocytosis, which was not followed by a change in morphology. This underscores the importance of understanding the role of infiltrating myeloid cells in different disease contexts and phases. Furthermore, we showed that our assay is a valuable tool for investigating myeloid cell interactions in a range of CNS neuroinflammatory conditions.
Insights
Peripheral myeloid cells influence brain microglia differently based on central nervous system (CNS) injury type and timing. Understanding these interactions is key for developing neuroprotective therapies for conditions like multiple sclerosis and stroke.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Peripherally derived myeloid cells infiltrate the central nervous system (CNS) during injury and disease, contributing to neuroinflammation.
- The phenotype and function of these infiltrating cells vary with injury type and disease phase, influencing interactions with resident microglia.
Purpose of the Study:
- To develop an in vitro system for investigating communication between peripheral myeloid cells and microglia.
- To uncover differences in myeloid cell-microglia crosstalk based on disease model (experimental autoimmune encephalomyelitis [EAE] and cerebral ischemia [pMCAO]) and disease timing.
Main Methods:
- Isolation of peripheral myeloid cells from EAE and pMCAO mouse models at different time points post-disease onset.
- Co-culture of isolated peripheral myeloid cells with primary microglia to assess phenotypic and gene expression changes.
- Analysis of microglial morphology and gene expression related to inflammatory and phagocytic pathways.
Main Results:
- Peripheral myeloid cells from acute EAE induced microglial morphological changes and increased inflammatory gene expression.
- Peripheral myeloid cells from chronic pMCAO induced inflammatory and phagocytic gene expression changes in microglia without altering morphology.
- Identified disease-specific and time-dependent alterations in myeloid cell-microglia interactions.
Conclusions:
- The impact of infiltrating myeloid cells on microglia is context-dependent, varying by disease model and phase.
- The developed in vitro assay is a valuable tool for studying myeloid cell interactions in various CNS neuroinflammatory conditions.
- Findings highlight the importance of considering disease context and timing for myeloid cell-mediated neuroinflammation and potential therapeutic strategies.
