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Neuronal autophagy aggravates microglial inflammatory injury by downregulating CX3CL1/fractalkine after ischemic stroke

Deng, Yi-Hao, He, Hong-Yun, Ren, Lu, Guo, Tao·2019·Neural Regeneration Research
DOI 10.4103/1673-5374.244793PMC PMC6301168
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Figure 1 Correlation between autophagy and CX3CL1/fractalkine expression or NF-κB p65 activation after ischemic stroke (western blot assay). Autophagic signaling in the penumbra was remarkably activated by ischemia within 6 hours(h) after cerebral ischemia (A, B); however, the autophagy level was obviously declined at 12 h after insult. At this time point, the NF-κB p65 expression level (D) was also decreased, but CX3CL1 expression (C) was contrarily increased. There is a trend that autophagy level was negatively correlated with CX3CL1 expression, but positively correlated with activation of inflammatory signaling (as shown in the red squares). Relative protein expression was expressed as the optical density ratio to β-actin. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. NF-κB: Nuclear factor kappa B; LC3B: light chain 3B.
Figure 1 Correlation between autophagy and CX3CL1/fractalkine expression or NF-κB p65 activation after ischemic stroke (western blot assay). Autophagic signaling in the penumbra was remarkably activated by ischemia within 6 hours(h) after cerebral ischemia (A, B); however, the autophagy level was obviously declined at 12 h after insult. At this time point, the NF-κB p65 expression level (D) was also decreased, but CX3CL1 expression (C) was contrarily increased. There is a trend that autophagy level was negatively correlated with CX3CL1 expression, but positively correlated with activation of inflammatory signaling (as shown in the red squares). Relative protein expression was expressed as the optical density ratio to β-actin. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. NF-κB: Nuclear factor kappa B; LC3B: light chain 3B.CC BY-NC-SA · PubMed Central
Figure 2 Effect of altered autophagy on CX3CL1 expression and inflammatory responses after ischemic stroke (western blot assay). Autophagy inducer Tat-Beclin 1 and autophagy inhibitor 3-MA were additionally administered in MCAO rats, separately. CX3CL1, Iba-1, and NF-κB p65 expression were detected 12 hours after insult. The results indicated that autophagy inhibition (A) dramatically enhanced CX3CL1 expression (B); meanwhile, both Iba-1 (C) and NF-κB p65 (D) expression levels were markedly declined. Compared with the MCAO group, CX3CL1 expression was further reduced after treatment with an autophagy inducer in the MCAO + Tat group; whereas, Iba-1 and NF-κB p65 were increasingly expressed. Relative protein expression was expressed as the optical density ratio to β-actin. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. MCAO: Middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1; NF-κB: nuclear factor kappa B.
Figure 2 Effect of altered autophagy on CX3CL1 expression and inflammatory responses after ischemic stroke (western blot assay). Autophagy inducer Tat-Beclin 1 and autophagy inhibitor 3-MA were additionally administered in MCAO rats, separately. CX3CL1, Iba-1, and NF-κB p65 expression were detected 12 hours after insult. The results indicated that autophagy inhibition (A) dramatically enhanced CX3CL1 expression (B); meanwhile, both Iba-1 (C) and NF-κB p65 (D) expression levels were markedly declined. Compared with the MCAO group, CX3CL1 expression was further reduced after treatment with an autophagy inducer in the MCAO + Tat group; whereas, Iba-1 and NF-κB p65 were increasingly expressed. Relative protein expression was expressed as the optical density ratio to β-actin. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. MCAO: Middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1; NF-κB: nuclear factor kappa B.CC BY-NC-SA · PubMed Central
Figure 3 Neuronal autophagy reduces CX3CL1 expression on neurons and activates microglial inflammatory responses after cerebral stroke. Immunofluorescence was performed to determine cellular localization of CX3CL1 and its effect on microglial inflammatory responses. The results showed that enhanced neuronal autophagy [A, E (MCAO + Tat group)] reduced CX3CL1 expression on neurons (B, F), and further boosted microglial activity (C, G). In contrast, inhibition of neuron autophagy improved the percentage of CX3CL1-positive neurons, and reduced the ratio of NF-κB p65-positive microglia (D, H). In A and B, green staining (DyLight 488) indicates LC3B and CX3CL1-positive cells, while red staining (Alexa Fluor® 594) indicates NeuN-positive cells and yellow (merged) indicated the LC3B and CX3CL1-positive neurons. In C, red indicates Iba-1-positive cells; blue indicates total cells; and the merged picture shows the percentage of activated microglia. In D, green staining (DyLight 488) indicates NF-κB p65-positive cells, while red staining (Alexa Fluor® 594) indicates Iba-1-positive cells and yellow (merged) indicates the ratio of NF-κB p65-positive microglia. Arrows indicate positive neurons or microglia. Scale bars: 10 μm. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. MCAO: Middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1; NF-κB: nuclear factor kappa B.
Figure 3 Neuronal autophagy reduces CX3CL1 expression on neurons and activates microglial inflammatory responses after cerebral stroke. Immunofluorescence was performed to determine cellular localization of CX3CL1 and its effect on microglial inflammatory responses. The results showed that enhanced neuronal autophagy [A, E (MCAO + Tat group)] reduced CX3CL1 expression on neurons (B, F), and further boosted microglial activity (C, G). In contrast, inhibition of neuron autophagy improved the percentage of CX3CL1-positive neurons, and reduced the ratio of NF-κB p65-positive microglia (D, H). In A and B, green staining (DyLight 488) indicates LC3B and CX3CL1-positive cells, while red staining (Alexa Fluor® 594) indicates NeuN-positive cells and yellow (merged) indicated the LC3B and CX3CL1-positive neurons. In C, red indicates Iba-1-positive cells; blue indicates total cells; and the merged picture shows the percentage of activated microglia. In D, green staining (DyLight 488) indicates NF-κB p65-positive cells, while red staining (Alexa Fluor® 594) indicates Iba-1-positive cells and yellow (merged) indicates the ratio of NF-κB p65-positive microglia. Arrows indicate positive neurons or microglia. Scale bars: 10 μm. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. MCAO: Middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1; NF-κB: nuclear factor kappa B.CC BY-NC-SA · PubMed Central
Figure 4 Effect of neuronal autophagy on production of inflammatory molecules after ischemic stroke (enzyme-linked immunosorbent assay). Tissues in the penumbra area were obtained 12 hours after insult to detect the production of inflammatory markers. (A–D) IL-1β, TNF-α, IL-6, and PGE2 production, respectively. Concentrations of inflammatory molecules in brain tissues from the MCAO group were markedly higher than those from the sham or MCAO + 3-MA groups, but notably lower than those from the MCAO + Tat group. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. IL: Interleukin; TNF-α: tumor necrosis factor alpha; PGE2: prostaglandin E2; MCAO: middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1.
Figure 4 Effect of neuronal autophagy on production of inflammatory molecules after ischemic stroke (enzyme-linked immunosorbent assay). Tissues in the penumbra area were obtained 12 hours after insult to detect the production of inflammatory markers. (A–D) IL-1β, TNF-α, IL-6, and PGE2 production, respectively. Concentrations of inflammatory molecules in brain tissues from the MCAO group were markedly higher than those from the sham or MCAO + 3-MA groups, but notably lower than those from the MCAO + Tat group. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. IL: Interleukin; TNF-α: tumor necrosis factor alpha; PGE2: prostaglandin E2; MCAO: middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1.CC BY-NC-SA · PubMed Central
Figure 5 Effect of neuronal autophagy on brain edema in ischemic stroke rats. To observe the effect of autophagy on ischemia-induced inflammatory edema, brain water content was assessed. The ratio of water content in brain tissues from MCAO + 3-MA group was obviously lower than that from MCAO + Tat or MCAO groups, and was similar to that of the sham group. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. MCAO: Middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1.
Figure 5 Effect of neuronal autophagy on brain edema in ischemic stroke rats. To observe the effect of autophagy on ischemia-induced inflammatory edema, brain water content was assessed. The ratio of water content in brain tissues from MCAO + 3-MA group was obviously lower than that from MCAO + Tat or MCAO groups, and was similar to that of the sham group. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. MCAO: Middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1.CC BY-NC-SA · PubMed Central
Figure 6 Effect of neuronal autophagy on cerebral infarct volume in rats with ischemic stroke. (A) To observe the effect of microglial inflammation on cerebral infarct volume after ischemic stroke, TTC staining was performed to assess infarct size. (B) Cerebral infarct volume was obviously reduced after treatment with the autophagy inhibitor of 3-MA compared with MCAO rats, and was similar to that observed in sham animals. In contrast, infarct volume was further expanded after administration with the autophagy inducer Tat. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. (C) Black squares indicate the penumbral area (derived from the third graph in the MCAO group from A). MCAO: Middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1; TTC: 2,3,5-triphenyltetrazolium chloride.
Figure 6 Effect of neuronal autophagy on cerebral infarct volume in rats with ischemic stroke. (A) To observe the effect of microglial inflammation on cerebral infarct volume after ischemic stroke, TTC staining was performed to assess infarct size. (B) Cerebral infarct volume was obviously reduced after treatment with the autophagy inhibitor of 3-MA compared with MCAO rats, and was similar to that observed in sham animals. In contrast, infarct volume was further expanded after administration with the autophagy inducer Tat. Data are presented as the mean ± SEM (n = 6; one-way analysis of variance followed by Dunett’s test). *P < 0.01. (C) Black squares indicate the penumbral area (derived from the third graph in the MCAO group from A). MCAO: Middle cerebral artery occlusion; 3-MA: 3-methyladenine; Tat: Tat-Beclin 1; TTC: 2,3,5-triphenyltetrazolium chloride.CC BY-NC-SA · PubMed Central

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Metadata

Authors
Deng, Y.-H., He, H.-Y., Ren, L., & Guo, T.
Venue
Neural Regeneration Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019
Volume
14
Issue
2
Pages
280
ISSN
1673-5374
DOI
10.4103/1673-5374.244793
PMC
PMC6301168
Cited by
69
References
7
Language
en

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Deng, Y.-H., He, H.-Y., Ren, L., & Guo, T. (2019). Neuronal autophagy aggravates microglial inflammatory injury by downregulating CX3CL1/fractalkine after ischemic stroke. Neural Regeneration Research. https://doi.org/10.4103/1673-5374.244793