IRF8 is a transcriptional determinant for microglial motility
Takahiro Masuda1, Nao Nishimoto, Daisuke Tomiyama
1Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Abstract:
Microglia, the resident immune cells of the central nervous system, are constitutively mobile cells that undergo rapid directional movement toward sites of tissue disruption. However, transcriptional regulatory mechanisms of microglial motility remain unknown. In the present study, we show that interferon regulatory factor-8 (IRF8) regulates microglial motility. We found that ATP and complement component, C5a, induced chemotaxis of IRF8 wild-type microglia. However, these responses were markedly suppressed in microglia lacking IRF8 (Irf8 (-/-)). In a consistent manner, phosphorylation of Akt (which plays a crucial role in ATP-induced chemotaxis) was abolished in Irf8 (-/-)microglia. Real-time polymerase chain reaction analysis revealed that motility-related microglial genes such as P2Y12 receptor were significantly suppressed in Irf8 (-/-)microglia. Furthermore, Irf8 (-/-)microglia exhibited a differential expression pattern of nucleotide-degrading enzymes compared with their wild-type counterparts. Overall, our findings suggest that IRF8 may regulate microglial motility via the control of microglial gene expression.
Insights
Interferon regulatory factor-8 (IRF8) controls microglial cell movement in the brain. Suppressing IRF8 reduces the ability of these immune cells to migrate towards injury sites, impacting their function.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
- Transcriptional Regulation
Background:
- Microglia are the primary immune cells in the central nervous system.
- Microglial cells are inherently mobile and migrate towards tissue damage.
- The transcriptional regulation of microglial motility is not well understood.
Purpose of the Study:
- To investigate the role of interferon regulatory factor-8 (IRF8) in regulating microglial motility.
- To elucidate the molecular mechanisms underlying IRF8-mediated microglial migration.
Main Methods:
- Chemotaxis assays using ATP and C5a as chemoattractants on wild-type and Irf8 knockout microglia.
- Analysis of Akt phosphorylation.
- Real-time polymerase chain reaction (PCR) to assess gene expression of motility-related genes (e.g., P2Y12 receptor) and nucleotide-degrading enzymes.
Main Results:
- ATP- and C5a-induced chemotaxis were significantly suppressed in microglia lacking IRF8 (Irf8 (-/-)).
- Akt phosphorylation, crucial for ATP-induced chemotaxis, was abolished in Irf8 (-/-) microglia.
- Expression of motility-related genes, including P2Y12 receptor, and nucleotide-degrading enzymes were altered in Irf8 (-/-) microglia.
Conclusions:
- Interferon regulatory factor-8 (IRF8) plays a critical role in regulating microglial motility.
- IRF8 appears to control microglial migration by modulating the expression of key genes involved in motility and cellular signaling.
- These findings provide insights into the transcriptional control of microglial immune responses in the central nervous system.
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