Myeloid cell IRF4 signaling protects neonatal brains from hypoxic ischemic encephalopathy

Abstract

Interferon regulatory factor 4 (IRF4), a transcription factor recognized as a key regulator of lymphoid and myeloid cell differentiation, has recently been recognized as a critical mediator of macrophage activation. Previously we have reported that IRF4 signaling is closely correlated with anti-inflammatory polarization of microglia in adult mice after stroke. However, IRF4's role in the inflammatory response in the immature brain is unknown. Using a model of neonatal hypoxic ischemic encephalopathy (HIE) we investigated the regulatory action of IRF4 signaling in the activation of microglia and monocytes after HIE. IRF4 myeloid cell conditional knockout (CKO) postnatal day 10 (P10) male pups were subjected to a 60-minute hypoxic-ischemic insult by the Rice-Vanucci model (RVM). IRF4 gene floxed mice (IRF4 fl/fl) were used as controls. Brain atrophy and behavioral deficits were measured 7 days after HIE. Flow cytometry (FC) was performed to examine central (microglial activation) and peripheral immune cell responses by both cell membrane and intracellular marker staining. Serum levels of cytokines were determined by ELISA. The results showed that IRF4 CKO pups had increased tissue loss and worse behavioral deficits than IRF4 fl/fl mice seven days after HIE. FC demonstrated significantly more infiltration of monocytes and neutrophils in the ischemic brains of IRF4 CKO vs IRF4 fl/fl pups. IRF4 CKO ischemic microglia were more pro-inflammatory as evidenced by higher expression of the proinflammatory marker CD68, and increased intracellular TNFα and IL-1β levels compared to controls. In addition, IRF4 deletion from myeloid cells resulted in increased levels of circulating pro-inflammatory cytokines and higher endothelial MMP9 expression after HIE. These data indicate that IRF4 signaling in myeloid cells plays a regulatory role in neuroinflammation and that deletion of myeloid IRF4 is detrimental to HIE injury, suggesting that IRF4 could serve as a potential therapeutic target for neonatal ischemic brain injury.

RETRACTED: H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation

“… 8 , 9 Moreover, more recent studies have demonstrated that IRF4 could affect neuroinflammation after ischemic stroke and may serve as a potential therapeutic target for ischemic brain injury. 10 , 11 Interestingly, it has been identified that IRF4 is positively regulated by KDM6B demethylase and thus mediates inflammatory response. 12 The involvement of IRF4 in the homeostasis of mature B cells and the progression of human non-small cell lung cancer have been illustrated in a prior study, and the mechanism was shown to be through the regulation of the expression and activity of Notch2.…”

Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE

“…Lastly, we did not test the effects of rh-CSF1 on female rat pups. There is increasing evidence suggests that HIE is a sexually dimorphic disease [74]. Future studies are warranted to validate the other neuroprotective functions and potential mechanisms as well as gender differences associated with CSF1 after HI.…”

“…The acute innate immune response is critical in regulating neonatal HIE injury. Due to gender differences in pro-and antiinflammatory response, male infants are more susceptible to HI insult and develop severer long-term cognitive deficits than females with comparable brain damage [74]. Microglial activation and accumulation were previously identified as pathological markers for HIE in human infants [75].…”

Dexmedetomidine‐up‐regulated microRNA‐381 exerts anti‐inflammatory effects in rats with cerebral ischaemic injury via the transcriptional factor IRF4

“…For instance, miR‐301 associated with IRF1 was indicated being implicated in the neuronal innate immune response 15 . Additionally, further studies have illustrated IRF4 as a transcriptional factor correlated with the inflammatory response in the brain and suggested it as a target for the injury of neonatal ischaemic brain 16 …”