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Death-associated protein kinase 1 mediates interleukin-1? production through regulating inlfammasome activation in Bv2 microglial cells and mice.

ABSTRACT: Interleukin-1? (IL-1?) plays a crucial role in mediating inflammation and innate immunity response in the central nervous system. Death-associated protein kinase 1 (DAPK1) was shown to be involved in several cellular processes. Here, we investigated the effects of DAPK1 on IL-1? production in microglial cells. We used a combination of in vitro (Bv2 microglial cell cultures) and in vivo (mice injected with amyloid-? (A?)) techniques to address the role of caspase-1 activation in release of IL-1?. DAPK1 involvement was postulated through genetic approaches and pharmacological blockade of this enzyme. We found that A?_25-35 stimulation induced IL-1? production and caspase-1 activation in LPS-primed Bv2 cells and mice. DAPK1 knockdown and catalytic activity inhibition reduced IL-1? maturation and caspase-1 activation, nevertheless, DAPK1 overexpression attenuated these effects. A?_25-35-induced lysosomal cathepsin B leakage was required for DAPK1 activation. Furthermore, repeated DAPK1 inhibitor treatment ameliorated the memory impairment in A?_25-35-injected mice. Taken together, our findings suggest that DAPK1 facilitates A?_25-35-induced IL-1? production through regulating caspase-1 activation in microglial cells.

SUBMITTER: Song L

PROVIDER: S-EPMC6028446 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Death-associated protein kinase 1 mediates interleukin-1β production through regulating inlfammasome activation in Bv2 microglial cells and mice.

Song Limin L Pei Lei L Hu Lisha L Pan Shangwen S Xiong Wei W Liu Min M Wu Yan Y Shang You Y Yao Shanglong S

Scientific reports 20180702 1

Interleukin-1β (IL-1β) plays a crucial role in mediating inflammation and innate immunity response in the central nervous system. Death-associated protein kinase 1 (DAPK1) was shown to be involved in several cellular processes. Here, we investigated the effects of DAPK1 on IL-1β production in microglial cells. We used a combination of in vitro (Bv2 microglial cell cultures) and in vivo (mice injected with amyloid-β (Aβ)) techniques to address the role of caspase-1 activation in release of IL-1β. ...[more]

PMID: 29967321

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Project description:BackgroundHypoxic-ischemic encephalopathy (HIE) is a serious birth complication with high incidence in both advanced and developing countries. Children surviving from HIE often have severe long-term sequela including cerebral palsy, epilepsy, and cognitive disabilities. The severity of HIE in infants is tightly associated with increased IL-1β expression and astrocyte activation which was regulated by transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel in the TRP family.MethodsNeonatal hypoxic ischemia (HI) and oxygen-glucose deprivation (OGD) were used to simulate HIE in vivo and in vitro. Primarily cultured astrocytes were used for investigating the expression of glial fibrillary acidic protein (GFAP), IL-1β, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and activation of the nucleotide-binding, oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome by using Western blot, q-PCR, and immunofluorescence. Brain atrophy, infarct size, and neurobehavioral disorders were evaluated by Nissl staining, 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and neurobehavioral tests (geotaxis reflex, cliff aversion reaction, and grip test) individually.ResultsAstrocytes were overactivated after neonatal HI and OGD challenge. The number of activated astrocytes, the expression level of IL-1β, brain atrophy, and shrinking infarct size were all downregulated in TRPV1 KO mice. TRPV1 deficiency in astrocytes attenuated the expression of GFAP and IL-1β by reducing phosphorylation of JAK2 and STAT3. Meanwhile, IL-1β release was significantly reduced in TRPV1 deficiency astrocytes by inhibiting activation of NLRP3 inflammasome. Additionally, neonatal HI-induced neurobehavioral disorders were significantly improved in the TRPV1 KO mice.ConclusionsTRPV1 promotes activation of astrocytes and release of astrocyte-derived IL-1β mainly via JAK2-STAT3 signaling and activation of the NLRP3 inflammasome. Our findings provide mechanistic insights into TRPV1-mediated brain damage and neurobehavioral disorders caused by neonatal HI and potentially identify astrocytic TRPV1 as a novel therapeutic target for treating HIE in the subacute stages (24 h).

Dataset Information

Death-associated protein kinase 1 mediates interleukin-1? production through regulating inlfammasome activation in Bv2 microglial cells and mice.

Publications

Death-associated protein kinase 1 mediates interleukin-1β production through regulating inlfammasome activation in Bv2 microglial cells and mice.

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