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The impact of single and pairwise Toll-like receptor activation on neuroinflammation and neurodegeneration

Rosenberger, Karen, Derkow, Katja, Dembny, Paul, Krüger, Christina, Schott, Eckart, Lehnardt, Seija·2014·Journal of Neuroinflammation
DOI 10.1186/s12974-014-0166-7PMC PMC4182775
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Figure 1 Activation of single and pairwise TLRs results in a distinct inflammatory response in microglia. Purified microglia were stimulated with LPS (100 ng/mL), Pam3CysSK4 (Pam, 100 ng/mL), loxoribine (lox, 1 mM), or CpG ODN (CpG, 1 μM) alone or simultaneously with pairwise combinations of the ligands, as indicated. PBS served as control. Supernatants were collected at indicated time points and analyzed by TNF-α ELISA; mean ± SEM of five independent experiments run with duplicates. Two-way ANOVA with Bonferroni-selected pairs of each individual compound vs. combination of compounds (*LPS vs. ligand combination; #Pam vs. ligand combination; †CpG vs. ligand combination; §lox vs. ligand combination). P*, #, †, § <0.05; P**, ##, ††, §§ <0.005; P***, ###, †††, §§§ <0.001.
Figure 1 Activation of single and pairwise TLRs results in a distinct inflammatory response in microglia. Purified microglia were stimulated with LPS (100 ng/mL), Pam3CysSK4 (Pam, 100 ng/mL), loxoribine (lox, 1 mM), or CpG ODN (CpG, 1 μM) alone or simultaneously with pairwise combinations of the ligands, as indicated. PBS served as control. Supernatants were collected at indicated time points and analyzed by TNF-α ELISA; mean ± SEM of five independent experiments run with duplicates. Two-way ANOVA with Bonferroni-selected pairs of each individual compound vs. combination of compounds (*LPS vs. ligand combination; #Pam vs. ligand combination; †CpG vs. ligand combination; §lox vs. ligand combination). P*, #, †, § <0.05; P**, ##, ††, §§ <0.005; P***, ###, †††, §§§ <0.001.CC BY · PubMed Central
Figure 2 Pairwise TLR activation results in a distinct profile of cytokines and chemokines in microglia. Purified microglia were stimulated with LPS (100 ng/mL), Pam3CysSK4 (Pam, 100 ng/mL), loxoribine (lox, 1 mM), or CpG ODN (CpG, 1 μM) alone or simultaneously with pairwise combinations of the ligands, as indicated. PBS served as control. Supernatants were analyzed by (A) TNF-α ELISA (mean ± SEM of five independent experiments run with duplicates) and flow cytometry-based multiple analyte detection for several cytokine/chemokine levels, as indicated (mean ± SEM of four independent experiments) after 24 h, or by (B) Griess reaction for NO content (mean ± SEM of five independent experiments run with duplicates) after 48 h. ANOVA with Bonferroni-selected pairs of each individual ligand vs. combination of ligands, as indicated. P* <0.05; P** <0.005; P*** <0.001; n.d., not detected.
Figure 2 Pairwise TLR activation results in a distinct profile of cytokines and chemokines in microglia. Purified microglia were stimulated with LPS (100 ng/mL), Pam3CysSK4 (Pam, 100 ng/mL), loxoribine (lox, 1 mM), or CpG ODN (CpG, 1 μM) alone or simultaneously with pairwise combinations of the ligands, as indicated. PBS served as control. Supernatants were analyzed by (A) TNF-α ELISA (mean ± SEM of five independent experiments run with duplicates) and flow cytometry-based multiple analyte detection for several cytokine/chemokine levels, as indicated (mean ± SEM of four independent experiments) after 24 h, or by (B) Griess reaction for NO content (mean ± SEM of five independent experiments run with duplicates) after 48 h. ANOVA with Bonferroni-selected pairs of each individual ligand vs. combination of ligands, as indicated. P* <0.05; P** <0.005; P*** <0.001; n.d., not detected.CC BY · PubMed Central
Figure 3 Impact of TLR4 activation by HSP60 on the inflammatory response in microglia in vitro . Primary microglia were stimulated with HSP60 (1 μg/mL), LPS (100 ng/mL), Pam3CysSK4 (Pam, 100 ng/mL), loxoribine (lox, 1 mM), or CpG ODN (CpG, 1 μM) alone or simultaneously with pairwise combinations of the ligands, as indicated. Supernatants were analyzed (A) by TNF-α ELISA at various time points, as indicated (mean ± SEM of two to four independent experiments run with duplicates) or (B) by flow cytometry-based multiple analyte detection for cytokine/chemokine levels, as indicated (mean ± SEM of three independent experiments run with duplicates) after 12 h. Data in (A) were analyzed by two-way ANOVA with Bonferroni-selected pairs of each individual compound vs. combination of compounds (*HSP60 vs. ligand combination; #Pam vs. ligand combination). P*, # <0.05; P** <0.005; P*** <0.001. Data in (B) were analyzed by ANOVA with Bonferroni-selected pairs of each individual compound vs. combination of compounds, as indicated. P* <0.05; P** <0.005; P*** <0.001; n.d., not detected.
Figure 3 Impact of TLR4 activation by HSP60 on the inflammatory response in microglia in vitro . Primary microglia were stimulated with HSP60 (1 μg/mL), LPS (100 ng/mL), Pam3CysSK4 (Pam, 100 ng/mL), loxoribine (lox, 1 mM), or CpG ODN (CpG, 1 μM) alone or simultaneously with pairwise combinations of the ligands, as indicated. Supernatants were analyzed (A) by TNF-α ELISA at various time points, as indicated (mean ± SEM of two to four independent experiments run with duplicates) or (B) by flow cytometry-based multiple analyte detection for cytokine/chemokine levels, as indicated (mean ± SEM of three independent experiments run with duplicates) after 12 h. Data in (A) were analyzed by two-way ANOVA with Bonferroni-selected pairs of each individual compound vs. combination of compounds (*HSP60 vs. ligand combination; #Pam vs. ligand combination). P*, # <0.05; P** <0.005; P*** <0.001. Data in (B) were analyzed by ANOVA with Bonferroni-selected pairs of each individual compound vs. combination of compounds, as indicated. P* <0.05; P** <0.005; P*** <0.001; n.d., not detected.CC BY · PubMed Central
Figure 4 Co-activation of TLR4 and TLR2 causes enhanced microglia-dependent neuronal injury in vitro. (A) Primary cortical neurons were supplemented with purified microglia. Co-cultures were stimulated with 100 ng/mL LPS, 100 ng/mL Pam3CysSK4 (Pam), 1 mM loxoribine (lox), or 0.1 μM CpG ODN (CpG) alone or with pairwise combinations of the ligands, as indicated. PBS served as control. After 72 h co-cultures were immunostained with NeuN Ab (neurons, red) and IB4 (microglia, green). Scale bar, 100 μm. (B) Cortical neurons alone or supplemented with microglia were incubated with the TLR ligands named above, as indicated. After 72 h, NeuN+ and IB4+ cells were quantified and expressed as relative neuronal viability and relative microglial viability, respectively, as indicated. Each condition was performed in duplicate and averaged. Mean ± SEM from four to five individual experiments with ANOVA followed by Bonferroni post-hoc test of control vs. each treatment and of single vs. pair-wise stimulation (relative neuronal viability: co-cultures: *; neurons: †, relative microglial viability: co-cultures *), as indicated. Two-way ANOVA with Bonferroni post-hoc test between indicated groups testing if the neurotoxic effect is dependent on microglia (#). P* <0.05; P** <0.005; P*** <0.001; P# <0.05; P## <0.005; P### <0.001; P† <0.05; P†† <0.005.
Figure 4 Co-activation of TLR4 and TLR2 causes enhanced microglia-dependent neuronal injury in vitro. (A) Primary cortical neurons were supplemented with purified microglia. Co-cultures were stimulated with 100 ng/mL LPS, 100 ng/mL Pam3CysSK4 (Pam), 1 mM loxoribine (lox), or 0.1 μM CpG ODN (CpG) alone or with pairwise combinations of the ligands, as indicated. PBS served as control. After 72 h co-cultures were immunostained with NeuN Ab (neurons, red) and IB4 (microglia, green). Scale bar, 100 μm. (B) Cortical neurons alone or supplemented with microglia were incubated with the TLR ligands named above, as indicated. After 72 h, NeuN+ and IB4+ cells were quantified and expressed as relative neuronal viability and relative microglial viability, respectively, as indicated. Each condition was performed in duplicate and averaged. Mean ± SEM from four to five individual experiments with ANOVA followed by Bonferroni post-hoc test of control vs. each treatment and of single vs. pair-wise stimulation (relative neuronal viability: co-cultures: *; neurons: †, relative microglial viability: co-cultures *), as indicated. Two-way ANOVA with Bonferroni post-hoc test between indicated groups testing if the neurotoxic effect is dependent on microglia (#). P* <0.05; P** <0.005; P*** <0.001; P# <0.05; P## <0.005; P### <0.001; P† <0.05; P†† <0.005.CC BY · PubMed Central
Figure 5 Simultaneous activation of TLR4 by HSP60 and of TLR7 by loxoribine causes enhanced neuronal injury . Co-cultures of neurons and microglia as well as neurons alone were stimulated with 1 μg/mL HSP60, 100 ng (A) or 1 μg (B) /mL LPS, 100 ng/mL Pam3CysSK4 (Pam), 1 mM loxoribine (lox), or 0.1 μM CpG ODN (CpG) alone or with pairwise combinations of the ligands, as indicated. PBS served as control. After 72 h, NeuN+ cells (A -C) or after 24 h, cells positive for activated caspase-3 (D) were quantified and expressed as relative neuronal viability or caspase-3+ cells/field, respectively. Each condition was performed in duplicate and averaged. Mean ± SEM from (A) three to four and (B, C) four individual experiments with ANOVA followed by Bonferroni post-hoc test of control vs. each treatment and of single vs. pair-wise stimulation (*), as indicated. (A) In addition, data were analyzed by two-way ANOVA with Bonferroni post-hoc test between indicated groups testing if effect is dependent on microglia (#). (D) Mean ± SEM from four individual experiments with ANOVA followed by Bonferroni post-hoc test of control vs. each treatment and of single vs. pairwise stimulation. Scale bar, 100 μm. P* <0.05; P** <0.005; P*** <0.001; P# <0.05; P## <0.005; P### <0.001.
Figure 5 Simultaneous activation of TLR4 by HSP60 and of TLR7 by loxoribine causes enhanced neuronal injury . Co-cultures of neurons and microglia as well as neurons alone were stimulated with 1 μg/mL HSP60, 100 ng (A) or 1 μg (B) /mL LPS, 100 ng/mL Pam3CysSK4 (Pam), 1 mM loxoribine (lox), or 0.1 μM CpG ODN (CpG) alone or with pairwise combinations of the ligands, as indicated. PBS served as control. After 72 h, NeuN+ cells (A -C) or after 24 h, cells positive for activated caspase-3 (D) were quantified and expressed as relative neuronal viability or caspase-3+ cells/field, respectively. Each condition was performed in duplicate and averaged. Mean ± SEM from (A) three to four and (B, C) four individual experiments with ANOVA followed by Bonferroni post-hoc test of control vs. each treatment and of single vs. pair-wise stimulation (*), as indicated. (A) In addition, data were analyzed by two-way ANOVA with Bonferroni post-hoc test between indicated groups testing if effect is dependent on microglia (#). (D) Mean ± SEM from four individual experiments with ANOVA followed by Bonferroni post-hoc test of control vs. each treatment and of single vs. pairwise stimulation. Scale bar, 100 μm. P* <0.05; P** <0.005; P*** <0.001; P# <0.05; P## <0.005; P### <0.001.CC BY · PubMed Central
Figure 6 mRNA expression of TLRs in response to activation of a single TLR in the CNS . C57BL/6J mice were injected intrathecally with 10 μg LPS (n = 9), 10 μg Pam3CysSK4 (Pam, n = 9), 10 μg imiquimod (Imi, n = 8), or 10 μg CpG ODN (CpG, n = 9). Intrathecal injection of 0.9% NaCl (ctrl, n = 9) served as control. After 12 h, brain tissue was analyzed for mRNA expression of TLRs and proinflammatory molecules, as indicated, by quantitative real-time PCR. Data are presented as delta CT (dCT = CTgene of interest – CTGapdh) of each mouse with median per group on reverse scale to visualize changes in mRNA levels. Fold increase (2-ddCT, with fold change >2 and <0.5 expressing biological significance) was calculated with the median of each group, setting the control to 1; ANOVA of log2 transformed dCT values followed by Bonferroni post-hoc test of control vs. treatment. P* <0.05; P** <0.005; P*** <0.001.
Figure 6 mRNA expression of TLRs in response to activation of a single TLR in the CNS . C57BL/6J mice were injected intrathecally with 10 μg LPS (n = 9), 10 μg Pam3CysSK4 (Pam, n = 9), 10 μg imiquimod (Imi, n = 8), or 10 μg CpG ODN (CpG, n = 9). Intrathecal injection of 0.9% NaCl (ctrl, n = 9) served as control. After 12 h, brain tissue was analyzed for mRNA expression of TLRs and proinflammatory molecules, as indicated, by quantitative real-time PCR. Data are presented as delta CT (dCT = CTgene of interest – CTGapdh) of each mouse with median per group on reverse scale to visualize changes in mRNA levels. Fold increase (2-ddCT, with fold change >2 and <0.5 expressing biological significance) was calculated with the median of each group, setting the control to 1; ANOVA of log2 transformed dCT values followed by Bonferroni post-hoc test of control vs. treatment. P* <0.05; P** <0.005; P*** <0.001.CC BY · PubMed Central
Figure 7 Activation of specific TLRs causes neurodegeneration and inflammation in the brain in vivo. (A, B) C57BL/6J mice were injected intrathecally with water (control, n = 7) or one of the four TLR ligands (10 μg LPS, n = 10; 40 μg Pam3CysSK4, Pam, n = 11; 136 μg loxoribine, Lox, n = 9; 10 μg CpG ODN, CpG, n = 10), as indicated. After 3 days, brains were analyzed by immunohistochemistry. (A) Representative micrographs of the cerebral cortex immunostained with NeuN Ab, neurofilament Ab, and Iba1 Ab to detect neurons, axons, and microglia, respectively. Scale bar, 100 μm, inset 50 μm. (B) NeuN+ cells of the cerebral cortex were quantified. The mean of six high power fields per cerebral cortex is expressed as NeuN+ cells per mm2; median with Kruskal-Wallis test followed by Bonferroni post-hoc test of control vs. treatment. P* <0.05; P** <0.005. (C) Representative micrographs of the cerebral cortex immunostained with an Ab against activated caspase-3. Cortical cells positive for activated caspase-3, as indicated by arrows, were quantified. The mean of six high power fields per cerebral cortex is expressed as caspase-3+ cells per mm2; median with Kruskal-Wallis test followed by Bonferroni post-hoc test of control vs. treatment. P*** <0.001. (D) C57BL/6J mice were injected intrathecally with 0.9% NaCl (control, n = 9) or one of the four TLR ligands (10 μg LPS, n = 9; 10 μg Pam3CysSK4, Pam, n = 9; 10 μg imiquimod, Imi, n = 8; 10 μg CpG ODN, CpG, n = 9), as indicated. After 12 h, cerebrospinal fluid (CSF) was obtained from the cistern magna. Leukocytes in the CSF were counted and are expressed as leukocytes per μL CSF. Median with Kruskal-Wallis test followed by Dunn’s multiple comparison test of control vs. treatment. P* <0.05; P** <0.005. (E) C57BL/6J mice were injected intrathecally with 0.9% NaCl (control, n = 4) or one of the four TLR ligands (10 μg LPS, n = 4; 10 μg Pam3CysSK4, Pam, n = 4; 10 μg loxoribine, Lox, n = 4; 10 μg CpG ODN, CpG, n = 4), as indicated. After 24 h, CSF was analyzed by flow cytometry-based multiple analyte detection for amounts of various cytokines/chemokines, as indicated. Median with Kruskal-Wallis test followed by Dunn’s multiple comparison test of control vs. treatment. P* <0.05.
Figure 7 Activation of specific TLRs causes neurodegeneration and inflammation in the brain in vivo. (A, B) C57BL/6J mice were injected intrathecally with water (control, n = 7) or one of the four TLR ligands (10 μg LPS, n = 10; 40 μg Pam3CysSK4, Pam, n = 11; 136 μg loxoribine, Lox, n = 9; 10 μg CpG ODN, CpG, n = 10), as indicated. After 3 days, brains were analyzed by immunohistochemistry. (A) Representative micrographs of the cerebral cortex immunostained with NeuN Ab, neurofilament Ab, and Iba1 Ab to detect neurons, axons, and microglia, respectively. Scale bar, 100 μm, inset 50 μm. (B) NeuN+ cells of the cerebral cortex were quantified. The mean of six high power fields per cerebral cortex is expressed as NeuN+ cells per mm2; median with Kruskal-Wallis test followed by Bonferroni post-hoc test of control vs. treatment. P* <0.05; P** <0.005. (C) Representative micrographs of the cerebral cortex immunostained with an Ab against activated caspase-3. Cortical cells positive for activated caspase-3, as indicated by arrows, were quantified. The mean of six high power fields per cerebral cortex is expressed as caspase-3+ cells per mm2; median with Kruskal-Wallis test followed by Bonferroni post-hoc test of control vs. treatment. P*** <0.001. (D) C57BL/6J mice were injected intrathecally with 0.9% NaCl (control, n = 9) or one of the four TLR ligands (10 μg LPS, n = 9; 10 μg Pam3CysSK4, Pam, n = 9; 10 μg imiquimod, Imi, n = 8; 10 μg CpG ODN, CpG, n = 9), as indicated. After 12 h, cerebrospinal fluid (CSF) was obtained from the cistern magna. Leukocytes in the CSF were counted and are expressed as leukocytes per μL CSF. Median with Kruskal-Wallis test followed by Dunn’s multiple comparison test of control vs. treatment. P* <0.05; P** <0.005. (E) C57BL/6J mice were injected intrathecally with 0.9% NaCl (control, n = 4) or one of the four TLR ligands (10 μg LPS, n = 4; 10 μg Pam3CysSK4, Pam, n = 4; 10 μg loxoribine, Lox, n = 4; 10 μg CpG ODN, CpG, n = 4), as indicated. After 24 h, CSF was analyzed by flow cytometry-based multiple analyte detection for amounts of various cytokines/chemokines, as indicated. Median with Kruskal-Wallis test followed by Dunn’s multiple comparison test of control vs. treatment. P* <0.05.CC BY · PubMed Central
Figure 8 Subsequent challenge with HSP60 does not exacerbate CNS damage induced by exogenous TLR ligands. C57BL/6J mice received two subsequent intrathecal injections. On day one 40 μL water (carrier), 40 μg Pam3CysSK4 (Pam), or 136 μg loxoribine (Lox) were injected. After 24 h, 40 μL PBS or 40 μg HSP60 were injected additionally (water + PBS n = 7; water + HSP60 n = 4; Pam + PBS n = 5; Lox + PBS n = 5; Pam + HSP60 n = 8; Lox + HSP60 n = 8). After a further 3 days, brains were analyzed by immunohistochemistry. (A, C) NeuN+ cells of the cerebral cortex were quantified, and the mean is expressed as NeuN+ cells per mm2; median with Kruskal-Wallis test followed by Bonferroni post-hoc test of control (water + PBS) vs. treatment or between the respective treatments, as indicated. P* <0.05; n.s.: not significant. (B, D) Brain sections of injected mice were immunostained with an Ab against activated caspase-3. Cortical cells positive for activated caspase-3 were quantified. The mean of six high power fields per cerebral cortex is expressed as caspase-3+ cells per mm2; median with Kruskal-Wallis test followed by Bonferroni post-hoc test of control (water + PBS) vs. treatment or between the respective treatments, as indicated. P* <0.05; n.s.: not significant. (E, F) Representative micrographs of the cerebral cortex immunostained with neurofilament Ab (NF) and Iba1 Ab to mark axons and microglia, respectively. Scale bar, 100 μm, inset 50 μm.
Figure 8 Subsequent challenge with HSP60 does not exacerbate CNS damage induced by exogenous TLR ligands. C57BL/6J mice received two subsequent intrathecal injections. On day one 40 μL water (carrier), 40 μg Pam3CysSK4 (Pam), or 136 μg loxoribine (Lox) were injected. After 24 h, 40 μL PBS or 40 μg HSP60 were injected additionally (water + PBS n = 7; water + HSP60 n = 4; Pam + PBS n = 5; Lox + PBS n = 5; Pam + HSP60 n = 8; Lox + HSP60 n = 8). After a further 3 days, brains were analyzed by immunohistochemistry. (A, C) NeuN+ cells of the cerebral cortex were quantified, and the mean is expressed as NeuN+ cells per mm2; median with Kruskal-Wallis test followed by Bonferroni post-hoc test of control (water + PBS) vs. treatment or between the respective treatments, as indicated. P* <0.05; n.s.: not significant. (B, D) Brain sections of injected mice were immunostained with an Ab against activated caspase-3. Cortical cells positive for activated caspase-3 were quantified. The mean of six high power fields per cerebral cortex is expressed as caspase-3+ cells per mm2; median with Kruskal-Wallis test followed by Bonferroni post-hoc test of control (water + PBS) vs. treatment or between the respective treatments, as indicated. P* <0.05; n.s.: not significant. (E, F) Representative micrographs of the cerebral cortex immunostained with neurofilament Ab (NF) and Iba1 Ab to mark axons and microglia, respectively. Scale bar, 100 μm, inset 50 μm.CC BY · PubMed Central

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Sorted by citations

Metadata

Authors
Rosenberger, K., Derkow, K., Dembny, P., Krüger, C., Schott, E., & Lehnardt, S.
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2014-09-20
Volume
11
Issue
1
ISSN
1742-2094
DOI
10.1186/s12974-014-0166-7
PMC
PMC4182775
Cited by
84
References
6
Language
en
Licence
creativecommons.org/licenses/by/4.0 (unspecified)

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