English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Objective:  Neuroinflammation  in utero  may result in life-long neurological disabilities. The molecular mechanisms whereby microglia contribute to this response remain incompletely understood.   Methods:  Lipopolysaccharide (LPS) or saline were administered intravenously to non-anesthetized chronically instrumented near-term fetal sheep to model fetal inflammation  in vivo . Microglia were then isolated from  in vivo  LPS and saline (naïve) exposed animals. To mimic the second hit of neuroinflammation, these microglia were then re-exposed to LPS  in vitro . Cytokine responses were measured  in vivo  and subsequently  in vitro  in the primary microglia cultures derived from these animals. We sequenced the whole transcriptome of naïve and second hit microglia and profiled their genetic expression to define molecular pathways disrupted during neuroinflammation.   Results:   In vivo  LPS exposure resulted in IL-6 increase in fetal plasma 3 h post LPS exposure. Even though not histologically apparent, microglia acquired a pro-inflammatory phenotype  in vivo  that was sustained and amplified  in vitro  upon second hit LPS exposure as measured by IL-1β response  in vitro  and RNAseq analyses. While NFKB and Jak-Stat inflammatory pathways were up regulated in naïve microglia, heme oxygenase 1 ( HMOX1 ) and Fructose-1,6-bisphosphatase ( FBP ) genes were uniquely differentially expressed in the second hit microglia. Compared to the microglia exposed to LPS  in vitro  only, the transcriptome of the  in vivo  LPS pre-exposed microglia showed a diminished differential gene expression in inflammatory and metabolic pathways prior and upon re-exposure to LPS  in vitro . Notably, this desensitization response was also observed in histone deacetylases ( HDAC )  1, 2, 4 , and  6 . Microglial calreticulin/LRP genes implicated in microglia-neuronal communication relevant for the neuronal development were up regulated in second hit microglia.   Discussion:  We identified a unique  HMOX1  down  and  FBP  up  phenotype of microglia exposed to the double-hit suggesting interplay of inflammatory and metabolic pathways. Our findings suggest that epigenetic mechanisms mediate this immunological and metabolic memory of the prior inflammatory insult relevant to neuronal development and provide new therapeutic targets for early postnatal intervention to prevent brain injury.

Fetal microglial phenotype in vitro carries memory of prior in vivo exposure to inflammation