News Release
Title
Dual Microglia Effects on Blood Brain Barrier Permeability Induced by Systemic
Inflammation
Summary
The research team led by Prof. Hiroaki WAKE (Department of Molecular Cell Biologyand Anatomy) of Graduate School of Medicine, Nagoya University (Dean: Kenji
Kadomatsu, M.D., Ph.D) found a novel function of microglia on the permeability of theBlood Brain Barrier.
Peripheral organ status and systemic circulation are increasingly recognized as factorsthat impact cognitive performance and neuronal disease. This can range from acute severe
illness and fever causing malaise and poor cognition, from sepsis causing subsequentneurological disease and cognitive failure, through to chronic systemic inflammation
associated with smoking, diabetes, chronic periodontitis and even aging, leading to anincreased risk of dementia or neurodegenerative disorders.
Although it is known that microglia respond to injury and systemic disease in the brain,
it is unclear if they modulate blood-brain barrier (BBB) integrity, which is critical for
regulating neuro-inflammatory responses. Here using the in vivo two photon
microscope, they visualized microglia and vessels in living mice, and demonstrate thatmicroglia respond to inflammation by migrating towards and accumulating aroundcerebral vessels, where they initially maintain BBB integrity via expression of the tightjunction protein Claudin-5 before switching, during sustained inflammation, tophagocytically remove astrocytic end-feet resulting in impaired BBB function.

Research Background
BBB function is essential to maintain the homeostasis of the brain environment. It has
been known that increased BBB permeability was observed in several neurological andpsychiatric diseases. In addition, microglia as sole immune cell has been recently focusedon their involvement in neurological and psychiatric diseases with their activation form.
However little is known how microglia can have the function for BBB permeability. Herein this study, the research team examined the role of microglial functions in regulation ofBBB integrity, focusing on changes of microglia depends on inflammation progression.
Using in vivo two-photon imaging, they showed that microglia migrated to the cerebral
vessels in response to systemic inflammation which was associated with increased BBB
permeability.
Research ResultsThe research team demonstrated that microglia respond to inflammation by migrating
towards and accumulating around cerebral vessels. It was also found that the chemokine
CCL5 produced by vascular endothelial cells attracts microglia to blood vessels during
early systemic inflammation (Figure 1). Those accumulations promote CLDN5
expression in microglia to form tight junction with endothelial cells, and thus protect BBB
integrity. Electron microscopy revealed that vessel-associated microglia directly
contacted with the endothelial cells in the auto-immune disease model mouse. Prolonged
inflammation results in microglia to be more activated phenotype, resulting in increased
phagocytic function to actually phagocyte astrocytic end-feet that resulting in impaired
BBB permeability. Furthermore, inhibition of microglia activation with minocycline
reduced increase BBB permeability during late phase of inflammation. Our results
implicate microglia as playing a dual role in BBB permeability during systemic infection
and inflammation, with important implications for understanding how systemic diseases
may adversely impact on neural circuits and brain functions (Figure 2).

Figure 1: Systemic inflammation triggers microglia migration to the cerebral vessels.
It was revealed that CCL5 is produced from endothelial cells during systemic
inflammation, and that attract microglia to the vessels.

Figure 2: Functions of microglia involved in changes of blood-brain barrier due tosystemic inflammation.
CLDN5 positive microglia maintain BBB integrity during early phase of inflammation.
Microglia phagocytosis astrocytic end-feet impaired BBB function in late phase.
Research summary and future perspective
Microglia accumulate in blood vessels in response to CCL5 signals in early phase ofsystemic inflammation. Microglia are involved in both the protection and impairment ofthe BBB, depending on inflammation progression. Inhibition of microglia activation

suppressed the BBB dysfunction. This result should help to contribute to thedevelopment of new preventive and therapeutic methods in diseases of the central
nervous system caused by systemic inflammation.
Publication
Koichiro Haruwaka1,2,3, Ako Ikegami1, Yoshihisa Tachibana1, Nobuhiko Ohno4,5,
Hiroyuki Konishi6, Akari Hashimoto1, Mami Matsumoto7,8, Daisuke Kato1,9, Riho Ono1,Hiroshi Kiyama6, Andrew J Moorhouse10, Junichi Nabekura2,3 and Hiroaki Wake1,9,11,12*
1. Division of System Neuroscience, Kobe University Graduate School of Medicine,Kobe, Japan
2. Division of Homeostatic Development, National Institute for Physiological Sciences,National Institutes of Natural Sciences, Okazaki, Japan
3. Department of Physiological Sciences, The Graduate School for Advanced Study,Hayama, Japan
4. Department of Anatomy, Division of Histology and Cell Biology, Jichi MedicalUniversity, Tochigi, Japan
5. Division of Ultrastructural Research, National Institute for Physiological Sciences,Okazaki, Japan
6. Department of Functional Anatomy and Neuroscience, Nagoya University GraduateSchool of Medicine, Nagoya, Japan
7. Section of Electron Microscopy, Supportive Center for Brain Research, National
Institute for Physiological Sciences, Okazaki, Japan
8. Department of Developmental and Regenerative Biology, Nagoya City University
Graduate School of Medical Sciences, Nagoya, Japan
9. Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate
School of Medicine, Nagoya, Japan
10. School of Medical Sciences, The University of New South Wales, Sydney, Australia
11. Core Research for Evolutional Science and Technology, Japan Science andTechnology Agency, Saitama, Japan
12. Precursory Research for Embryonic Science and Technology, Japan Science andTechnology Agency, Saitama, Japan.
Dual Microglia Effects on Blood Brain Barrier Permeability Induced by Systemic
Inflammation

Nature Communications
DOI：10.1038/s41467-019-13812-z

Japanese ver.
https://www.med.nagoya-u.ac.jp/medical_J/research/pdf/Nat_Com_191220.pdf