Journal Article

Mitochondrial DNA enhance innate immune responses in neuromyelitis optica by monocyte recruitment and activation

Okuno, Tatsusada, Kumanogoh, Atsushi, Mochizuki, Hideki, Beppu, Shohei, Sugiyama, Yasuko, Shiraishi, Naoyuki, Yamashita, Kazuya, Sumi, Hisae, Tada, Satoru, Sugimoto, Tomoyuki, Koda, Toru, Nakatsuji, Yuji, Sakakibara, Kaori, Kinoshita, Makoto, Fujimura, Harutoshi, Shimizu, Mikito, Sakakibara, Shuhei, Ishikura, Teruyuki, Murata, Hisashi

2020

Overview

Although recent studies indicate the involvement of monocytes in accelerating the lesion formation of neuromyelitis optica spectrum disorder (NMOSD), the precise mechanism of the innate immune system activation remains elusive. Thus, in this study, we aimed to clarify the mechanisms of NMOSD pathogenesis from the viewpoint of innate immunity activation. We established anti-AQP4 recombinant autoantibodies (Ab) from plasmablasts in NMOSD patient’s CSF. Human astrocytes treated with anti-AQP4 Ab produced a significant amount of CCL2 and contributed to the efficient recruitment of monocytes. Moreover, mitochondrial DNA (mtDNA), which activated monocytes via Toll-like receptor 9 (TLR9), was released from astrocytes treated with anti-AQP4 Ab. MtDNA further enhanced CCL2 production by monocytes, and it was demonstrated that mtDNA concentration correlated with the efficiency of monocyte recruitment in the CSF of NMOSD patients. In conclusion, these observations highlight that mtDNA which was released from astrocytes damaged by anti-AQP4 Ab has a central role in establishing the inflammatory loop of monocyte recruitment and activation via an innate immunity pathway.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/371 / 631/250/38 / Adult / Aged / Antibodies - pharmacology / Aquaporin 4 / Aquaporin 4 - immunology / Astrocytes / Astrocytes - drug effects / Astrocytes - immunology / Autoantibodies / Cell activation / Cerebrospinal fluid / Chemokine CCL2 - metabolism / Deoxyribonucleic acid / DNA / DNA, Mitochondrial - genetics / Female / HEK293 Cells / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunity, Innate / Inflammation / Innate immunity / Middle Aged / Mitochondria - genetics / Mitochondrial DNA / Monocyte chemoattractant protein 1 / Monocytes / Monocytes - drug effects / Monocytes - immunology / multidisciplinary / Neuromyelitis / Neuromyelitis Optica - genetics / Neuromyelitis Optica - immunology / Recruitment / Science / Science (multidisciplinary) / TLR9 protein / Toll-Like Receptor 9 - metabolism / Toll-like receptors