Dataset Information

Bosutinib Attenuates Inflammation via Inhibiting Salt-Inducible Kinases in Experimental Model of Intracerebral Hemorrhage on Mice.

ABSTRACT: BACKGROUND AND PURPOSE:Intracerebral hemorrhage (ICH) is a subtype of stroke with highest mortality and morbidity. Pronounced inflammation plays a significant role in the development of the secondary brain injury after ICH. Recently, SIK-2 (salt-inducible kinase-2) was identified as an important component controlling inflammatory response. Here we sought to investigate the role of SIK-2 in post-ICH inflammation and potential protective effects of SIK-2 inhibition after ICH. METHODS:Two hundred and ninety-three male CD-1 mice were used. ICH was induced via injection of 30 ?L of autologous blood. Recombinant SIK-2 was administrated 1 hour after ICH intracerebroventricularly. SIK-2 small interfering RNA was injected intracerebroventricularly 24 hours before ICH. Bosutinib, a clinically approved tyrosine kinase inhibitor with affinity to SIK-2, was given intranasally 1 hour or 6 hours after ICH. Effects of treatments were evaluated by neurological tests and brain water content calculation. Molecular pathways were investigated by Western blots and immunofluorescence studies. RESULTS:Endogenous SIK-2 was expressed in microglia and neurons. SIK-2 expression was reduced after ICH. Exogenous SIK-2 aggravated post-ICH inflammation, leading to brain edema and the neurobehavioral deficits. SIK-2 inhibition attenuated post-ICH inflammation, reducing brain edema and ameliorating neurological dysfunctions. Bosutinib inhibited SIK-2-attenuating ICH-induced brain damage. Protective effects of Bosutinib were mediated, at least partly, by CRTC3 (cyclic amp-response element binding protein-regulated transcription coactivator 3)/cyclic amp-response element binding protein/NF-?B (nuclear factor-?B) pathway. CONCLUSIONS:SIK-2 participates in inflammation induction after ICH. SIK-2 inhibition via Bosutinib or small interfering RNA decreased inflammation, attenuating brain injury. SIK-2 effects are, at least partly, mediated by CRTC3-cyclic amp-response element binding protein-NF-?B signaling pathway.

SUBMITTER: Ma L

PROVIDER: S-EPMC5679716 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Bosutinib Attenuates Inflammation via Inhibiting Salt-Inducible Kinases in Experimental Model of Intracerebral Hemorrhage on Mice.

Ma Li L Manaenko Anatol A Ou Yi-Bo YB Shao An-Wen AW Yang Shu-Xu SX Zhang John H JH

Stroke 20171010 11

<h4>Background and purpose</h4>Intracerebral hemorrhage (ICH) is a subtype of stroke with highest mortality and morbidity. Pronounced inflammation plays a significant role in the development of the secondary brain injury after ICH. Recently, SIK-2 (salt-inducible kinase-2) was identified as an important component controlling inflammatory response. Here we sought to investigate the role of SIK-2 in post-ICH inflammation and potential protective effects of SIK-2 inhibition after ICH.<h4>Methods</h ...[more]

PMID: 29018127

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Project description:Macrophages switch to an anti-inflammatory, 'regulatory'-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of 'regulatory'-like macrophages at sites of inflammation. In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of 'regulatory'-like macrophages. Treatment of macrophages with bosutinib or dasatinib elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor ? (TNF?) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or dasatinib express higher levels of markers of 'regulatory'-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and dasatinib were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and dasatinib on macrophage polarization are the result of the inhibition of the salt-inducible kinases. Consistent with the present finding, bosutinib and dasatinib induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and dasatinib on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2). In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and dasatinib that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs.

Project description:The NLRP3 (NALP3, cryopyrin) inflammasome, a key component of the innate immune system, facilitates caspase-1 and interleukin (IL)-1? processing, which amplifies the inflammatory response. Here, we investigated whether NLRP3 knockdown decreases neutrophil infiltration, reduces brain edema, and improves neurological function in an intracerebral hemorrhage (ICH) mouse model. We also determined whether mitochondrial reactive oxygen species (ROS) governed by mitochondrial permeability transition pores (mPTPs) would trigger NLRP3 inflammasome activation following ICH.ICH was induced by injecting autologous arterial blood (30?l) into a mouse brain. NLRP3 small interfering RNAs were administered 24 hours before ICH. A mPTP inhibitor (TRO-19622) or a specific mitochondria ROS scavenger (Mito-TEMPO) was coinjected with the blood. In naive animals, rotenone, which is a respiration chain complex I inhibitor, was applied to induce mitochondrial ROS production, and followed by TRO-19622 or Mito-TEMPO treatment. Neurological deficits, brain edema, enzyme-linked immunosorbent assay, Western blot, in vivo chemical cross-linking, ROS assay, and immunofluorescence were evaluated.ICH activated the NLRP3 inflammasome. NLRP3 knockdown reduced brain edema and decreased myeloperoxidase (MPO) levels at 24 hours, and improved neurological functions from 24 to 72 hours following ICH. TRO-19622 or Mito-TEMPO reduced ROS, NLRP3 inflammasome components, and MPO levels following ICH. In naive animals, rotenone administration induced mPTP formation, ROS generation, and NLRP3 inflammasome activation, which were then reduced by TRO-19622 or Mito-TEMPO.The NLRP3 inflammasome amplified the inflammatory response by releasing IL-1? and promoting neutrophil infiltration following ICH. Mitochondria ROS may be a major trigger of NLRP3 inflammasome activation. The results of our study suggest that the inhibition of the NLRP3 inflammasome may effectively reduce the inflammatory response following ICH.ANN NEUROL 2014;75:209-219.

Dataset Information

Bosutinib Attenuates Inflammation via Inhibiting Salt-Inducible Kinases in Experimental Model of Intracerebral Hemorrhage on Mice.

Publications

Bosutinib Attenuates Inflammation via Inhibiting Salt-Inducible Kinases in Experimental Model of Intracerebral Hemorrhage on Mice.

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