Rh-IFN-? attenuates neuroinflammation and improves neurological function by inhibiting NF-?B through JAK1-STAT1/TRAF3 pathway in an experimental GMH rat model.

ABSTRACT: Neuroinflammation occurs after germinal matrix hemorrhage (GMH) and induces secondary brain injury. Interferon-? (IFN-?) has been shown to exert anti-inflammatory effects in infectious diseases via activating IFNAR and its downstream signaling. We aimed to investigate the anti-inflammatory effects of Recombinant human IFN-? (rh-IFN-?) and the underlying mechanisms in a rat GMH model. Two hundred and eighteen P7 rat pups of both sexes were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Rh-IFN-? was administered intraperitoneally. Small interfering RNA (siRNA) of IFNAR, and siRNA of tumor necrosis factor receptor associated factor 3 (TRAF3) were administered through intracerebroventricular (i.c.v.) injections. JAK1 inhibitor ruxolitinib was given by oral lavage. Post-GMH evaluation included neurobehavioral function, Nissl staining, Western blot analysis, and immunofluorescence. Our results showed that endogenous IFN-? and phosphorylated IFNAR levels were increased after GMH. Administration of rh-IFN-? improved neurological functions, attenuated neuroinflammation, inhibited microglial activation, and ameliorated post-hemorrhagic hydrocephalus after GMH. These observations were concomitant with IFNAR activation, increased expression of phosphorylated JAK1, phosphorylated STAT1 and TRAF3, and decreased levels of phosphorylated NF-?B, IL-6 and TNF-?. Specifically, knockdown of IFNAR, JAK1 and TRAF3 abolished the protective effects of rh-IFN-?. In conclusion, our findings demonstrated that rh-IFN-? treatment attenuated neuroinflammation, neurological deficits and hydrocephalus formation through inhibiting microglial activation after GMH, which might be mediated by IFNAR/JAK1-STAT1/TRAF3/NF-?B signaling pathway. Rh-IFN-? may be a promising therapeutic agent to attenuate brain injury via its anti-inflammatory effect.

SUBMITTER: Li P 

PROVIDER: S-EPMC6591046 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature