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Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats

Zuo, Yuchun, Huang, Lei, Enkhjargal, Budbazar, Xu, Weilin, Umut, Ocak, Travis, Zachary D., Zhang, Guangyu, Tang, Jiping, Liu, Fei, Zhang, John H.·2019·Journal of Neuroinflammation
DOI 10.1186/s12974-019-1432-5PMC PMC6385420
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Abstract

BACKGROUND: Subarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high mortality and disabilities. Retinoid X receptor (RXR) has been shown to be neuroprotective against ischemia/reperfusion injury. This study aimed to investigate the effects of the selective RXR agonist bexarotene on neuroinflammation in a rat model of SAH. METHODS: Two hundred male Sprague-Dawley rats were used. The endovascular perforation induced SAH. Bexarotene was administered intraperitoneally at 1 h after SAH induction. To investigate the underlying mechanism, the selective RXR antagonist UVI3003 and RXR siRNA or SIRT6 inhibitor OSS128167 was administered via intracerebroventricular 1 h before SAH induction. Post-SAH assessments including SAH grade, neurological score, brain water content, Western blot, and immunofluorescence were performed. RESULTS: The endogenous RXR and sirtuin 6 (SIRT6) protein levels were increased after SAH. Bexarotene treatment significantly reduced brain edema and improved the short-/long-term neurological deficit after SAH. Mechanistically, bexarotene increased the levels of PPARγ and SIRT6; decreased the expression of phosphorylated FoxO3a (p-FoxO3a), IL-6, IL-1β, and TNF-a; and inhibited the microglia activation and neutrophils infiltration at 24 h after SAH. Either UVI3003, OSS128167, or RXR siRNA abolished the neuroprotective effects of bexarotene and its regulation on protein levels of PPARγ/SIRT6/p-FoxO3a after SAH. CONCLUSIONS: The activation of RXR by bexarotene attenuated neuroinflammation and improved neurological deficits after SAH. The anti-neuroinflammatory effect was at least partially through regulating PPARγ/SIRT6/FoxO3a pathway. Bexarotene may be a promising therapeutic strategy in the management of SAH patients.

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Fig. 1 Experimental design and animal groups. RXR retinoid X receptor, SIRT6 sirtuin 6, Bexa bexarotene, UVI3003 RXR antagonist, OSS128167 selective sirtuin 6 inhibitor, IHC immunohistochemistry, WB western blot, i.p intraperitoneal injection, i.c.v intracerebroventricular injection, SAH subarachnoid hemorrhage
Fig. 1 Experimental design and animal groups. RXR retinoid X receptor, SIRT6 sirtuin 6, Bexa bexarotene, UVI3003 RXR antagonist, OSS128167 selective sirtuin 6 inhibitor, IHC immunohistochemistry, WB western blot, i.p intraperitoneal injection, i.c.v intracerebroventricular injection, SAH subarachnoid hemorrhageCC BY · PubMed Central
Fig. 2 Temporal expressions and cellular localization of endogenous brain RXR and SIRT6 after SAH. a Representative western blot bands and quantitative analyses of RXR time course in the left hemisphere after SAH. b Representative western blot bands and quantitative analyses of SIRT6 time course in the left hemisphere after SAH. *P < 0.05 vs sham group. Error bars were represented as mean ± SD. n = 6 per group. c Double immunofluorescence staining for RXR (green) in the neuron (NeuN, red), astrocytes (GFAP, red), and microglia (Iba-1, red) in the left basal cortex at 24 h after SAH. d Double immunofluorescence staining for SIRT6 (red) in the neuron (NeuN, green), astrocytes (GFAP, green), and microglia (Iba-1, green) in the left basal cortex at 24 h after SAH. n = 2 per group. Scale bar, 50 μm. DAPI indicates 4′,6-diamidino2-phenylindole; GFAP glial fibrillary acidic protein, Iba-1 ionized calcium binding adaptor molecule-1, NeuN neuronal nuclear
Fig. 2 Temporal expressions and cellular localization of endogenous brain RXR and SIRT6 after SAH. a Representative western blot bands and quantitative analyses of RXR time course in the left hemisphere after SAH. b Representative western blot bands and quantitative analyses of SIRT6 time course in the left hemisphere after SAH. *P < 0.05 vs sham group. Error bars were represented as mean ± SD. n = 6 per group. c Double immunofluorescence staining for RXR (green) in the neuron (NeuN, red), astrocytes (GFAP, red), and microglia (Iba-1, red) in the left basal cortex at 24 h after SAH. d Double immunofluorescence staining for SIRT6 (red) in the neuron (NeuN, green), astrocytes (GFAP, green), and microglia (Iba-1, green) in the left basal cortex at 24 h after SAH. n = 2 per group. Scale bar, 50 μm. DAPI indicates 4′,6-diamidino2-phenylindole; GFAP glial fibrillary acidic protein, Iba-1 ionized calcium binding adaptor molecule-1, NeuN neuronal nuclearCC BY · PubMed Central
Fig. 3 Bexarotene attenuated the neurobehavioral deficits and brain edema at 24 h after SAH. a Modified Garcia score and beam balance score. b Brain water content in the left hemisphere, right hemisphere, cerebellum, and brain stem. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexarotene
Fig. 3 Bexarotene attenuated the neurobehavioral deficits and brain edema at 24 h after SAH. a Modified Garcia score and beam balance score. b Brain water content in the left hemisphere, right hemisphere, cerebellum, and brain stem. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexaroteneCC BY · PubMed Central
Fig. 4 The effects of bexarotene on microglia/macrophage activation and neutrophil infiltration at 24 h after SAH. a, d Representative microphotograph of immunofluorescence staining of Iba-1 (green) and MPO (green) at 24 h after SAH. b, e Quantitative analyses of Iba-1- and MPO-positive cells in the basal cortex at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle. Error bars were represented as mean ± SD. n = 4 per group. c, f Representative western blot bands and quantitative analyses of Iba-1 and MPO protein levels in the left hemisphere at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexarotene
Fig. 4 The effects of bexarotene on microglia/macrophage activation and neutrophil infiltration at 24 h after SAH. a, d Representative microphotograph of immunofluorescence staining of Iba-1 (green) and MPO (green) at 24 h after SAH. b, e Quantitative analyses of Iba-1- and MPO-positive cells in the basal cortex at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle. Error bars were represented as mean ± SD. n = 4 per group. c, f Representative western blot bands and quantitative analyses of Iba-1 and MPO protein levels in the left hemisphere at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexaroteneCC BY · PubMed Central
Fig. 5 The effects of bexarotene on the RXR/ PPARγ interaction after SAH. IP assay of RXR/PPARγ interaction in left hemisphere at 24 h after SAH. Bexa bexarotene
Fig. 5 The effects of bexarotene on the RXR/ PPARγ interaction after SAH. IP assay of RXR/PPARγ interaction in left hemisphere at 24 h after SAH. Bexa bexaroteneCC BY · PubMed Central
Fig. 6 Bexarotene improved the long-term neurological deficit after SAH. a Rotarod test of 5 rpm and 10 rpm. b Escape latency and swim distance of water maze test. c Representative heat map in probe test showed bexarotene treated SAH spent more time in probe quadrant. d Probe quadrant duration. e velocity of probe trial. *P < 0.05, vs. sham group; #P < 0.05, vs. SAH + vehicle group. Data was represented as mean ± SD. n = 9 per group. Bexa bexarotene
Fig. 6 Bexarotene improved the long-term neurological deficit after SAH. a Rotarod test of 5 rpm and 10 rpm. b Escape latency and swim distance of water maze test. c Representative heat map in probe test showed bexarotene treated SAH spent more time in probe quadrant. d Probe quadrant duration. e velocity of probe trial. *P < 0.05, vs. sham group; #P < 0.05, vs. SAH + vehicle group. Data was represented as mean ± SD. n = 9 per group. Bexa bexaroteneCC BY · PubMed Central
Fig. 7 RXR selective inhibitor UVI3003 reversed the anti-neuroinflammation effects of bexarotene and its regulation on downstream signaling proteins of PPARγ/SIRT6/p-FoxO3a at 24 h after SAH. a Representative western blot bands. b–h Quantitative analyses of RXR, PPARγ, SIRT6, p-FoxO3a, IL-1β, IL-6, and TNF-α in the left hemisphere at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle, and &&P < 0.01 vs. SAH + BEXA + vehicle. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexarotene
Fig. 7 RXR selective inhibitor UVI3003 reversed the anti-neuroinflammation effects of bexarotene and its regulation on downstream signaling proteins of PPARγ/SIRT6/p-FoxO3a at 24 h after SAH. a Representative western blot bands. b–h Quantitative analyses of RXR, PPARγ, SIRT6, p-FoxO3a, IL-1β, IL-6, and TNF-α in the left hemisphere at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle, and &&P < 0.01 vs. SAH + BEXA + vehicle. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexaroteneCC BY · PubMed Central
Fig. 8 RXR knockdown reversed the anti-neuroinflammation effects of bexarotene at 24 h after SAH. a Representative Western blot bands. b–h Quantitative analyses of RXR, PPARγ, SIRT6, p-FoxO3a, IL-1β, IL-6, and TNF-α in the left hemisphere at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle, and @@P < 0.01 vs. SAH + BEXA + scramble siRNA. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexarotene
Fig. 8 RXR knockdown reversed the anti-neuroinflammation effects of bexarotene at 24 h after SAH. a Representative Western blot bands. b–h Quantitative analyses of RXR, PPARγ, SIRT6, p-FoxO3a, IL-1β, IL-6, and TNF-α in the left hemisphere at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle, and @@P < 0.01 vs. SAH + BEXA + scramble siRNA. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexaroteneCC BY · PubMed Central
Fig. 9 SIRT6 inhibitor OSS128167 reversed the anti-neuroinflammation effect of bexarotene and its regulation on downstream signaling protein of p-FoxO3a at 24 h after SAH. a Representative Western blot bands. b–h Quantitative analyses of RXR, PPARγ, SIRT6, p-FoxO3a, IL-1β, IL-6, and TNF-α in the left hemisphere at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle, and &&P < 0.01 vs. SAH + Bexa + vehicle. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexarotene
Fig. 9 SIRT6 inhibitor OSS128167 reversed the anti-neuroinflammation effect of bexarotene and its regulation on downstream signaling protein of p-FoxO3a at 24 h after SAH. a Representative Western blot bands. b–h Quantitative analyses of RXR, PPARγ, SIRT6, p-FoxO3a, IL-1β, IL-6, and TNF-α in the left hemisphere at 24 h after SAH. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle, and &&P < 0.01 vs. SAH + Bexa + vehicle. Error bars were represented as mean ± SD. n = 6 per group. Bexa bexaroteneCC BY · PubMed Central
Fig. 10 Bexarotene attenuated IL-1β-positive cells and MPO-positive cells infiltration at 24 h after SAH, which were abolished by UVI3003 or OSS128167. a Representative microphotography of IL-1β immunofluorescence staining in the left basal cortex. b Quantitative analyses of IL-1β-positive cells at 24 h after SAH. c Representative microphotography of MPO immunofluorescence staining in the left basal cortex. d Quantitative analyses of MPO-positive cells at 24 h after SAH. Scale bar, 50 μm. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle, and &&P < 0.01 vs. SAH + Bexa + vehicle. Error bars were represented as mean ± SD. n = 4 per group. Bexa bexarotene
Fig. 10 Bexarotene attenuated IL-1β-positive cells and MPO-positive cells infiltration at 24 h after SAH, which were abolished by UVI3003 or OSS128167. a Representative microphotography of IL-1β immunofluorescence staining in the left basal cortex. b Quantitative analyses of IL-1β-positive cells at 24 h after SAH. c Representative microphotography of MPO immunofluorescence staining in the left basal cortex. d Quantitative analyses of MPO-positive cells at 24 h after SAH. Scale bar, 50 μm. **P < 0.01 vs. sham, ##P < 0.01 vs. SAH + vehicle, and &&P < 0.01 vs. SAH + Bexa + vehicle. Error bars were represented as mean ± SD. n = 4 per group. Bexa bexaroteneCC BY · PubMed Central

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Metadata

Authors
Zuo, Y., Huang, L., Enkhjargal, B., Xu, W., Umut, O., Travis, Z. D., Zhang, G., Tang, J., Liu, F., & Zhang, J. H.
ORCID
Zhang, John H.
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2019-02-21
Volume
16
Issue
1
ISSN
1742-2094
DOI
10.1186/s12974-019-1432-5
PMC
PMC6385420
Cited by
88
References
54
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (tdm)

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