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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
Interferon regulatory factor 8/interferon consensus sequence binding protein is a critical transcription factor for
Makoto Horiuchi1, Kouji Wakayama, Aki Itoh
1Department of Neurology, University of California Davis, School of Medicine, 4860 Y Street, Sacramento, CA 95817, USA.
Background:
Recent fate-mapping studies establish that microglia, the resident mononuclear phagocytes of the CNS, are distinct in origin from the bone marrow-derived myeloid lineage. Interferon regulatory factor 8 (IRF8, also known as interferon consensus sequence binding protein) plays essential roles in development and function of the bone marrow-derived myeloid lineage. However, little is known about its roles in microglia.
Methods:
The CNS tissues of IRF8-deficient mice were immunohistochemically analyzed. Pure microglia isolated from wild-type and IRF8-deficient mice were studied in vitro by proliferation, immunocytochemical and phagocytosis assays. Microglial response in vivo was compared between wild-type and IRF8-deficient mice in the cuprizon-induced demyelination model.
Results:
Our analysis of IRF8-deficient mice revealed that, in contrast to compromised development of IRF8-deficient bone marrow myeloid lineage cells, development and colonization of microglia are not obviously affected by loss of IRF8. However, IRF8-deficient microglia demonstrate several defective phenotypes. In vivo, IRF8-deficient microglia have fewer elaborated processes with reduced expression of IBA1/AIF1 compared with wild-type microglia, suggesting a defective phenotype. IRF8-deficient microglia are significantly less proliferative in mixed glial cultures than wild-type microglia. Unlike IRF8-deficient bone marrow myeloid progenitors, exogenous macrophage colony stimulating factor (colony stimulating factor 1) (M-CSF (CSF1)) restores their proliferation in mixed glial cultures. In addition, IRF8-deficient microglia exhibit an exaggerated growth response to exogenous granulocyte-macrophage colony stimulating factor (colony stimulating factor 2) (GM-CSF (CSF2)) in the presence of other glial cells. IRF8-deficient microglia also demonstrate altered cytokine expressions in response to interferon-gamma and lipopolysaccharide in vitro. Moreover, the maximum phagocytic capacity of IRF8-deficient microglia is reduced, although their engulfment of zymosan particles is not overtly impaired. Defective scavenging activity of IRF8-deficient microglia was further confirmed in vivo in the cuprizone-induced demyelination model in mice.
Conclusions:
This study is the first to demonstrate the essential contribution of IRF8-mediated transcription to a broad range of microglial phenotype. Microglia are distinct from the bone marrow myeloid lineage with respect to their dependence on IRF8-mediated transcription.
Insights
Interferon regulatory factor 8 (IRF8) is crucial for microglial function, impacting their proliferation, cytokine expression, and phagocytosis. Loss of IRF8 impairs microglia but not their development, highlighting distinct roles from myeloid cells.
Area of Science:
- Neuroimmunology
- Cell Biology
- Molecular Biology
Background:
- Microglia, the CNS immune cells, originate differently from bone marrow myeloid cells.
- Interferon regulatory factor 8 (IRF8) is vital for myeloid lineage development and function.
- The specific role of IRF8 in microglia remains largely unknown.
Purpose of the Study:
- To investigate the role of IRF8 in microglial development and function.
- To compare IRF8's function in microglia versus bone marrow-derived myeloid cells.
- To elucidate the impact of IRF8 deficiency on microglial phenotypes.
Main Methods:
- Immunohistochemical analysis of CNS tissues from IRF8-deficient mice.
- In vitro studies of isolated microglia (proliferation, immunocytochemistry, phagocytosis assays).
- In vivo assessment in a cuprizone-induced demyelination model.
Main Results:
- Microglial development and colonization are unaffected by IRF8 deficiency.
- IRF8-deficient microglia exhibit defective phenotypes: reduced processes, lower proliferation, altered cytokine expression, and impaired phagocytic capacity.
- IRF8-deficient microglia show altered responses to colony-stimulating factors (CSF1, CSF2).
Conclusions:
- IRF8 plays an essential role in regulating diverse microglial functions.
- Microglia's dependence on IRF8-mediated transcription differs from that of bone marrow myeloid lineage cells.
- This study reveals critical, distinct functions of IRF8 in microglia.
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