Mast cell TNF receptors regulate responses to Mycoplasma pneumoniae in surfactant protein A (SP-A)−/− mice Bethany J. Hsia, PhD, Julie G. Ledford, PhD,

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Presentation transcript:

Mast cell TNF receptors regulate responses to Mycoplasma pneumoniae in surfactant protein A (SP-A)−/− mice Bethany J. Hsia, PhD, Julie G. Ledford, PhD, Erin N. Potts-Kant, BS, Vinayak S. Nikam, BS, Njira L. Lugogo, MD, W. Michael Foster, PhD, Monica Kraft, MD, Soman N. Abraham, PhD, Jo Rae Wright, PhD Journal of Allergy and Clinical Immunology Volume 130, Issue 1, Pages 205-214.e2 (July 2012) DOI: 10.1016/j.jaci.2012.03.002 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Mycoplasma pneumoniae (Mp) positivity and TNF-α levels in asthmatic samples. A, TNF-α in human BAL fluid (fold over healthy subjects). ∗∗P < .01, asthmatic patients (high) versus asthmatic patients (low) and both asthma groups versus healthy subjects. B, RT-PCR for M pneumoniae–specific P1 adhesin and dilution of samples into SP-4 broth to verify M pneumoniae positivity in subjects. ∗P < .05, asthmatic patients (high) versus healthy subjects and asthmatic patients (low). C, TNF values in M pneumoniae–positive and M pneumoniae–negative samples. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2012 130, 205-214.e2DOI: (10.1016/j.jaci.2012.03.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 MCs in Mycoplasma pneumoniae (Mp)–infected lung tissue. Mice were instilled with saline (A) or M pneumoniae (B-E) and lungs were analyzed by means of immunohistochemistry 3 days after infection for MCs. Fig 2, C, MCs adjacent to the large airway. Fig 2, D, Extracellular MC granules (arrow). Fig 2, E, MCs in the lung parenchyma. F, Total number of tissue MCs assessed in WT versus SP-A−/− lungs (n = 5 each). ∗P < .05. Journal of Allergy and Clinical Immunology 2012 130, 205-214.e2DOI: (10.1016/j.jaci.2012.03.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Contribution of MCs to AHR and inflammation. A and B, Three days after Mycoplasma pneumoniae (Mp), AHR to methacholine challenge was measured by using the Flexivent system. Mean percentage over baseline for highest methacholine dose is shown in parentheses. ∗∗P < .01 and ^P < .01, 3 independent experiments per graph. C and D, Cells in BAL fluid 12 hours (Fig 3, C) or 72 hours (Fig 3, D) after infection. ∗P < .05 versus WT M pneumoniae unless otherwise noted. E, Total protein in BAL fluid, n ≥ 12 mice per group. Journal of Allergy and Clinical Immunology 2012 130, 205-214.e2DOI: (10.1016/j.jaci.2012.03.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 AHR in WT bone marrow–derived MC–reconstituted infected mice. A, Engraftment of MCs (arrows) verified by means of immunohistochemistry in lung tissue 1 month after injection. B, Quantification of engraftment. C, AHR to methacholine challenge was measured by using the Flexivent system. Mean percentage over baseline for highest methacholine dose is shown in parentheses. ∗∗P < .01, #P < .01, and ^P < 0.05, 3 independent experiments per graph. D, TNF-α in BAL fluid 12 hours after infection. ∗P < .05 versus WT Mycoplasma pneumoniae group, n ≥ 12 mice per group. Mp, Mycoplasma pneumoniae. Journal of Allergy and Clinical Immunology 2012 130, 205-214.e2DOI: (10.1016/j.jaci.2012.03.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 TNF-α production from Mycoplasma pneumoniae (Mp)–stimulated MCs. Nonstimulated (NS) or M pneumoniae–stimulated (multiplicity of infection, 100:1) bone marrow–derived MCs with and without SP-A (40 μg/mL) were analyzed over 14 hours (A) or 1 hour (B). Supernatants were analyzed for TNF-α release by means of ELISA; cell pellets were assessed by using RT-PCR for TNF-α transcription. ∗P < .05. Data are representative of 3 independent experiments. Journal of Allergy and Clinical Immunology 2012 130, 205-214.e2DOI: (10.1016/j.jaci.2012.03.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Contribution of MC TNF-R to AHR and mucus. Mice were engrafted with TNF-α−/− or TNF-R−/− bone marrow–derived MCs. A, AHR to methacholine challenge was measured by using the Flexivent system. Mean percentage over baseline for highest methacholine dose is shown in parentheses. ∗∗, ^, #, $P < .01, 3 independent experiments per graph, n ≥ 12 mice per group. B and C, PAS-stained airways in infected mice (original magnification ×10) were scored. ∗∗∗P < .001, ∗∗P < .01, and ∗P < .05; n = 7-12 sections per group. Mp, Mycoplasma pneumoniae. Journal of Allergy and Clinical Immunology 2012 130, 205-214.e2DOI: (10.1016/j.jaci.2012.03.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Contribution of MCs to Mycoplasma pneumoniae (Mp) clearance. M pneumoniae burden in lung tissue at day 3 was measured by using RT-PCR for the M pneumoniae–specific P1 adhesin gene relative to β-actin and is expressed as fold over WT M pneumoniae–infected mice. ∗P < .05, n ≥ 12 mice per group. Journal of Allergy and Clinical Immunology 2012 130, 205-214.e2DOI: (10.1016/j.jaci.2012.03.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 Protective role of SP-A against Mycoplasma pneumoniae (Mp)–induced AHR. SP-A binds M pneumoniae in the large airway and prevents overcolonization. If SP-A is dysfunctional, more M pneumoniae burden results in TNF-α overproduction from epithelial cells, alveolar macrophages(AMs), and/or neutrophils (PMNs). TNF-α encounters tissue MCs in the submucosa, which are stimulated through the TNF-R to release mediators that contribute to high levels of AHR. Journal of Allergy and Clinical Immunology 2012 130, 205-214.e2DOI: (10.1016/j.jaci.2012.03.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 AHR in KitW-sh/W-sh–engrafted mice. Mice were engrafted with MCs for 1 month. AHR to methacholine challenge was assessed by using the Flexivent system. ∗∗P < .01. Mp, Mycoplasma pneumoniae. Journal of Allergy and Clinical Immunology 2012 130, 205-214.e2DOI: (10.1016/j.jaci.2012.03.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions