The platelet NLRP3 inflammasome is upregulated in sickle cell disease via HMGB1/TLR4 and Bruton tyrosine kinase by Sebastian Vogel, Taruna Arora, Xunde.

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The platelet NLRP3 inflammasome is upregulated in sickle cell disease via HMGB1/TLR4 and Bruton tyrosine kinase by Sebastian Vogel, Taruna Arora, Xunde Wang, Laurel Mendelsohn, James Nichols, Darlene Allen, Arun S. Shet, Christian A. Combs, Zenaide M. N. Quezado, and Swee Lay Thein BloodAdv Volume 2(20):2672-2680 October 23, 2018 ©2018 by American Society of Hematology

Sebastian Vogel et al. Blood Adv 2018;2:2672-2680 ©2018 by American Society of Hematology

Platelet caspase-1 activity is upregulated in SCD patients in steady state and further increased during an acute pain crisis. Platelet caspase-1 activity is upregulated in SCD patients in steady state and further increased during an acute pain crisis. Platelet caspase-1 activity is upregulated in SCD patients in steady state (SS) compared with healthy controls (A) and is further elevated when measured in the same SCD patients experiencing an acute pain crisis (paired samples) (B). Data are shown as median with IQR and minimum and maximum values (A) and before-after plot (B). The P values were calculated using the Mann-Whitney U test (A) and the Wilcoxon-signed rank test (B). Sebastian Vogel et al. Blood Adv 2018;2:2672-2680 ©2018 by American Society of Hematology

NLRP3 and ASC colocalize in platelets derived from SCD patients. NLRP3 and ASC colocalize in platelets derived from SCD patients. (A) In platelets derived from SCD patients in steady state, intraplatelet ASC (red) colocalizes with NLRP3 (green), as demonstrated with immunofluorescence staining and confocal laser scanning microscopy. Images show maximum intensity projection of confocal images Z-stacks and are representative of 3 independent preparations per group. Scale bar, 2 μm. (B) Quantification of NLRP3/ASC colocalization using the Pearson correlation coefficient. Data are shown as median with IQR and minimum and maximum values from n = 3 subjects per group. The P value was calculated using the Mann-Whitney U test. Sebastian Vogel et al. Blood Adv 2018;2:2672-2680 ©2018 by American Society of Hematology

Plasma from SCD patients in steady state and crisis upregulates the NLRP3 inflammasome in platelets from healthy subjects. Plasma from SCD patients in steady state and crisis upregulates the NLRP3 inflammasome in platelets from healthy subjects. (A) PPP from SCD patients in steady state (SS) upregulates platelet caspase-1 activity compared with PPP from healthy controls. (B) Platelet caspase-1 activation is further elevated upon incubation with PPP from SCD patients in crisis compared with PPP from the same patients in SS. (C) An NLRP3 inhibitor (MCC950) inhibits caspase-1 activity of platelets in the presence of PPP from healthy subjects and SCD patients in SS and crisis. Data are shown as median with IQR and minimum and maximum values (A,C) and before-after plot (B). The P values were calculated using the Mann-Whitney U test (A), the Wilcoxon signed-rank test (B), and the Friedman test with Dunn multiple comparisons (C). **P < .01, ***P < .001. Sebastian Vogel et al. Blood Adv 2018;2:2672-2680 ©2018 by American Society of Hematology

SCD-induced upregulation of the platelet NLRP3 inflammasome depends on HMGB1/TLR4 and BTK. (A) HMGB1 plasma levels are elevated in SCD patients in steady state (SS) compared with healthy controls. SCD-induced upregulation of the platelet NLRP3 inflammasome depends on HMGB1/TLR4 and BTK. (A) HMGB1 plasma levels are elevated in SCD patients in steady state (SS) compared with healthy controls. (B) HMGB1 plasma levels are elevated in SCD patients in crisis compared with the same patients in SS. (C) HMGB1 plasma levels in healthy subjects and SCD patients in SS and crisis correlate with plasma-induced platelet caspase-1 activity. (D) A neutralizing anti-HMGB1 antibody (HMGB1 AB) or the HMGB1 inhibitor glycyrrhizin inhibits platelet caspase-1 activity induced by PPP from SCD patients in SS and crisis and has no effect in the presence of PPP from healthy controls. (E) Preincubation of platelets with the TLR4 inhibitor TAK242 inhibits platelet caspase-1 activity induced by PPP from SCD patients in SS and crisis. Preincubation of platelets with the BTK inhibitor ibrutinib or a combination of TAK242, MCC950, and ibrutinib inhibits platelet caspase-1 activity in the presence of PPP from healthy and SCD subjects. Data are shown as median with IQR and minimum and maximum values (A,D-E), before-after plot (B), and scatter plot with linear regression (C). Statistical tests used: Mann-Whitney U test (A), Wilcoxon signed-rank test (B), Spearman rank correlation, ρ = correlation coefficient (C), and Friedman test with Dunn multiple comparisons (D-E). Sebastian Vogel et al. Blood Adv 2018;2:2672-2680 ©2018 by American Society of Hematology

NLRP3 and BTK regulate platelet aggregation in sickle cell mice. NLRP3 and BTK regulate platelet aggregation in sickle cell mice. (A) Platelet caspase-1 activity is increased in homozygous Townes SCD mice compared with heterozygous and control mice. (B) IV injection of MCC950 (50 mg/kg body weight) or ibrutinib (10 mg/kg body weight) suppresses upregulated platelet caspase-1 activity in homozygous SCD mice. (C) Platelet aggregation is elevated in homozygous Townes SCD mice compared with heterozygous and control mice. (D) IV injection of MCC950 or ibrutinib interferes with upregulated platelet aggregation in homozygous SCD mice. Data are shown as mean ± SD of the results from ≥3 separate experiments (n ≥ 3 mice per group). *P < .05, **P < .01, ***P < .001, 1-way ANOVA with Bonferroni post hoc test (A,C), 2-way ANOVA with Bonferroni post hoc test (B,D). Sebastian Vogel et al. Blood Adv 2018;2:2672-2680 ©2018 by American Society of Hematology