RelB controls adaptive responses of astrocytes during sterile inflammation

• Published in: Glia Vol. 67; no. 8; pp. 1449 - 1461
• Main Authors: Gupta, Angela S., Waters, Michael R., Biswas, Debolina D., Brown, Lashardai N., Surace, Michael J., Floros, Constantinos, Siebenlist, Ulrich, Kordula, Tomasz
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.08.2019
• Subjects: Adaptive Immunity - physiology; Animals; astrocytes; Astrocytes - immunology; Brain - immunology; Cytokines - metabolism; Epigenesis, Genetic; HEK293 Cells; Humans; IL‐1β; Immune Tolerance - physiology; Inflammation - metabolism; Mice, Transgenic; Neuroimmunomodulation; neuroinflammation; Phosphorylation; RelB; Sirtuin 1 - metabolism; tolerance; Transcription Factor RelB - genetics; Transcription Factor RelB - metabolism; astrocytes; IL-1β; neuroinflammation; tolerance; RelB
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23619

In response to brain injury or infections, astrocytes become reactive, undergo striking morphological and functional changes, and secrete and respond to a spectrum of inflammatory mediators. We asked whether reactive astrocytes also display adaptive responses during sterile IL‐1β‐induced neuroinflammation, which may limit tissue injury associated with many disorders of the central nervous system. We found that astrocytes display days‐to‐weeks long specific tolerance of cytokine genes, which is coordinated by NF‐κB family member, RelB. However, in contrast to innate immune cells, astrocytic tolerance does not involve epigenetic silencing of the cytokine genes. Establishment of tolerance depends on persistent higher levels of RelB in tolerant astrocytes and its phosphorylation on serine 472. Mechanistically, this phosphorylation prevents efficient removal of RelB from cytokine promoters by IκBα and helps to establish tolerance. Importantly, ablation of RelB from astrocytes in mice abolishes tolerance during experimental neuroinflammation in vivo. Main Points Astrocytes display days‐to‐weeks long tolerance of cytokine genes in vitro and in vivo. This tolerance is coordinated by an NF‐κB family member RelB. Deletion of RelB from astrocytes abolishes tolerance during experimental neuroinflammation in vivo.