Leukemia Inhibitory Factor Attenuates Hypoxic-Ischemic White Matter Injury via NLRP3 Inflammasome Activity Suppressing Through the Nrf2/HO-1 Pathway.

BACKGROUND

Inhibiting neuroinflammatory damage is an effective strategy for treating preterm white matter injury (PWMI). Leukemia inhibitory factor (LIF) can ameliorate (HI) induced white matter injury; however, the neuroprotective effects and mechanisms of LIF remain unclear. This study aimed to determine whether NOD-like receptor thermal protein domain associated protein (NLRP3)-dependent pyroptosis is involved in PWMI pathogenesis.

METHODS

We established an oxygen-glucose deprivation (OGD) cell model and an HI induced brain white matter injury neonatal mouse model. RNA sequencing (RNA-seq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses examined differentially expressed genes in oxygen-glucose deprivation/reoxygenation (OGD/R) challenged CTX TNA2 rat astrocytes. The changes and effects of proteins were confirmed in neonatal rats and . Cell viability assays, reactive oxygen species (ROS) assays, apoptosis assays, and immunoblot were used to confirm LIF-mediated its neuroprotective effect against HI-induced white matter injury .

RESULTS

RNA-seq and KEGG analyses indicated OGD/R enriched NLRP3 inflammasome-related genes (validated by and models), showing that NLRP3-dependent pyroptosis proteins (apoptosis-associated speck-like protein contain a CARD (ASC), NLRP3, active caspase 1, IL-1β, IL-18, and N-terminal fragment of gasdermin D (GSDMD-N)) were all increased by HI or OGD/R. LIF upregulated HO-1 expression by activating Nrf2 via the MAPK and Akt kinase pathways and significantly decreased OGD/R-induced ROS production. NLRP3-dependent pyroptosis proteins were suppressed in the LIF group compared with those in the OGD/R and HI groups. Zinc protophyrin, an HO-1 inhibitor, partially abolished LIF-mediated viability enhancement in rat astrocytes.

CONCLUSION

NLRP3-dependent pyroptosis plays a role in PWMI pathogenesis; moreover, LIF mitigates OGD/R-induced pyroptosis-dependent neurotoxicity by upregulating HO-1 expression in rat astrocytes.