Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury

Abstract

Background: Interleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxicischemic (HI) brain injury and elucidate the underlying mechanisms of action. Methods: The brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia and treated with IL-33 at a dose of 0.2 μg/day i.p. for 3 days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells and cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes. Results: The expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 days after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation. Conclusions: The activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries

“…Several post-mortem and preclinical studies have highlighted the importance of astrocytes and their potential interactions with MG [ 60 , 61 ]. These include a study that demonstrated using transgenic, and pharmacologic approaches in vivo and in vitro that astrocyte derived IL33 is an endogenous neuroprotective agent in a mouse more of NE including by HI including by supporting the M2-like phenotype of MG [ 132 ]. In an EoP model, the existence of a tripartite glial circuits has been demonstrated: the OPC maturation blockade by MG activation required an astrocytic reactivity, via an overproduction of cyclo-oxygenase-2 (COX)-2 [ 133 ].…”

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System

“…ST2 or IL-33 deficiency exacerbates ischemic brain injury after MCAO in mice (60,61). Conversely, exogenous IL-33 treatment protects mice against experimental ischemic stroke (9, 63-65) and neonatal hypoxic ischemic brain injury (62). Mechanistically, IL-33 does not directly act on neurons.…”

“…In the mouse model of ischemic stroke induced by middle cerebral artery occlusion (MCAO), IL-33 mRNA and protein expression are obviously upregulated in lesions, and mature oligodendrocytes and astrocytes are responsible for this upregulation (9,(60)(61)(62).…”

Perinatal Brain Injury and Inflammation: Lessons from Experimental Murine Models

“…IL-10 released from astrocytes suppressed neuronal apoptosis in response to HIE via the TLR2/NFκB pathway in a rat model of hypoxia-ischemia [ 114 ]. Similarly, the astrocyte-derived IL-33 following HIE is upregulated in the first 24 h post-HIE, and the ST2 receptor, the receptor for IL-33, was shown to be upregulated in astrocytes post-HIE [ 115 ]. Importantly, exogenous delivery of IL-33 via intraperitoneal injection alleviated the resultant brain injury 7 days post-HIE.…”