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Tetracycline-induced mitohormesis mediates disease tolerance against influenza

ABSTRACT: Mitohormesis defines the increase in fitness mediated by adaptive responses to a mild mitochondrial stress. Tetracyclines inhibit not only bacterial but also mitochondrial translation, thus imposing a low level of mitochondrial stress to eukaryotic cells. We show here that the mitochondrial stress response induced by 2 tetracyclins (Tet1, Tet2) improves survival and disease tolerance against lethal influenza virus (IFV) infection. Tolerance to IFV infection is associated with the induction of genes involved in lung epithelial cell and cilia function and with the down-regulation of inflammatory and immune related gene sets in the lung, liver, and kidney.

ORGANISM(S): Mus musculus

PROVIDER: GSE174124 | GEO | 2022/09/14

REPOSITORIES: GEO

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Mitohormesis reprograms macrophage metabolism to enforce tolerance [BMDM_tolerance_RNAseq]

Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.

2021-04-04 | GSE169730 | GEO