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TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation
Gregory S. Whitehead, … , Hideki Nakano, Donald N. Cook
Gregory S. Whitehead, … , Hideki Nakano, Donald N. Cook
Published July 31, 2017
Citation Information: J Clin Invest. 2017;127(9):3313-3326. https://doi.org/10.1172/JCI90890.
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Research Article Immunology Inflammation

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

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Abstract

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma.

Authors

Gregory S. Whitehead, Seddon Y. Thomas, Karim H. Shalaby, Keiko Nakano, Timothy P. Moran, James M. Ward, Gordon P. Flake, Hideki Nakano, Donald N. Cook

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Figure 5

TNF from CD11c+ macrophages acts on radioresistant AECs to reprogram them and promote allergic sensitization.

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TNF from CD11c+ macrophages acts on radioresistant AECs to reprogram the...
(A and B) TNF in BALF after instillation of LPS/OVA into WT and Myd88–/– mice (A) or Myd88fl/fl mice crossed to Sftpc-cre mice or Cd11c-cre mice to delete Myd88 in AECs or Cd11c-expressing cells, respectively (B) (n = 8 mice per group). (C) TNF in medium alone (Med), or culture supernatants of alveolar (Alv) macrophages, interstitial (Int) macrophages, monocytes (Mon), and cDCs purified by FACS from lungs of LPS/OVA-treated mice (n = 6 mice per group). (D) Cell numbers for the indicated leukocytes in airways of WT and TNFR1/2-DKO (KO) reciprocal bone marrow chimeric mice sensitized with OVA with or without LPS and subsequently challenged with aerosolized OVA (n = 6 mice per group). (A–D) Data represent mean values ± SEM and were confirmed by at least 1 repeat experiment. *P < 0.05, **P < 0.01, ***P < 0.001; Kruskal-Wallis 1-way ANOVA with Dunn’s multiple comparison test. (E) Heatmap showing genes whose induction in AECs by inhaled LPS was more than 1.5-fold different in WT and TNFR1/2-DKO mice, P < 0.01 (see Methods for details on statistical analysis).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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