Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide Weishan Huang, PhD, J. Luis Morales,

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Presentation transcript:

Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide Weishan Huang, PhD, J. Luis Morales, PhD, Victor P. Gazivoda, BS, Avery August, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 4, Pages 1197-1205 (April 2016) DOI: 10.1016/j.jaci.2015.08.056 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 The absence of ITK and BTK enhances LPS-induced hypothermia, neutrophil influx, and mast cell–derived TNF-α. A, Change in core body temperature induced by LPS. P value by ANOVA. B, Number of indicated cells in peritoneal lavage. C, MFI of TNF-α expression by peritoneal cells stimulated in vitro (gating strategy shown in Fig E2). P value by t test. n ≥ 3. MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2016 137, 1197-1205DOI: (10.1016/j.jaci.2015.08.056) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 ITK and BTK negatively regulate LPS-induced hypothermia via mast cells. A, Preformed TNF-α mRNA in BMMCs. P value by t test. B, Steady-state TNF-α synthesis by BMMCs. C and D, Proinflammatory cytokine mRNA and secretion induced by (Fig 2, C) 100 ng/mL or (Fig 2, D) 1 μg/mL LPS. E, LPS-induced hypothermia in Sash mice reconstituted with BMMCs. P values by ANOVA. BFA, Brefeldin A. Journal of Allergy and Clinical Immunology 2016 137, 1197-1205DOI: (10.1016/j.jaci.2015.08.056) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 ITK/BTK kinase activity is required to attenuate LPS-induced TNF-α production in mast cells and hypothermia. Effect of ITK/BTK inhibitor on preformed (A) and LPS-induced TNF-α mRNA in mouse BMMCs (B), LPS-induced TNF-α expression in mouse PLMCs (C), and LPS-induced murine hypothermia (D). E, Effect of ITK/BTK inhibitor on LPS-induced TNF-α mRNA in human CBMCs. n ≥ 3, P by t test (columns) or ANOVA (curves). DMSO, Dimethyl sulfoxide. Journal of Allergy and Clinical Immunology 2016 137, 1197-1205DOI: (10.1016/j.jaci.2015.08.056) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 ITK and BTK differentially regulate LPS-induced gene expression in mast cells. LPS-induced transcriptomic profiles are normalized to control levels in WT, Itk−/−, Btk−/−, and Itk/Btk−/− BMMCs, respectively. A, Venn diagrams of genes with >2- or 4-fold LPS-induced changes. B, Principal-component analysis of genes with >4-fold changes. Arrows indicate LPS-induced changes in WT (black) and Itk/Btk−/− (red) BMMCs. Ellipse (blue dashed) shows area with 95% CI with WT and Itk/Btk−/− controls. Journal of Allergy and Clinical Immunology 2016 137, 1197-1205DOI: (10.1016/j.jaci.2015.08.056) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Hyperactive canonical NF-κB signaling by Itk−/−Btk−/− BMMCs in response to LPS. A, Heat map of NF-κB target genes that changed >4-fold in response to PBS or LPS (arrow indicates TNF-α). B, Western blot analysis for the indicated components of the NF-κB pathway (representative results of ≥2 experiments). Fold changes below respective blots relative to WT at time 0 are shown. C, Analysis for nuclear translocation of p65 in PBS- or LPS-treated BMMCs. P values by t test. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2016 137, 1197-1205DOI: (10.1016/j.jaci.2015.08.056) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Hyperactive PI3K/Akt and p38 signaling by Itk−/−Btk−/− BMMCs in response to LPS. WT and Itk−/−Btk−/− BMMCs were stimulated with LPS and analyzed for the activation of Akt and the indicated MAPKs by Western blotting. Fold changes below the respective blots compared with WT time 0 are shown. Data represent results from ≥2 independent experiments. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2016 137, 1197-1205DOI: (10.1016/j.jaci.2015.08.056) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 PI3K/Akt and MNK1 are required for hyperactive TNF-α production and enhanced hypothermia in the absence of ITK and BTK. Effectors of PI3K/Akt (A) and MNK inhibitors (B) on LPS-induced TNF-α mRNA in BMMCs (i), TNF-α protein expression in PLMCs (ii), and hypothermia in Itk−/−Btk−/− mice (iii). n ≥ 3, P by t test (columns) or ANOVA (curves). DMSO, Dimethyl sulfoxide. Journal of Allergy and Clinical Immunology 2016 137, 1197-1205DOI: (10.1016/j.jaci.2015.08.056) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions