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

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 4

TNF signaling through TNFR1 promotes type 2, but not type 17, cell differentiation.

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TNF signaling through TNFR1 promotes type 2, but not type 17, cell diffe...
(A–C) Mice receiving adoptive transfer of OVA-specific CD4+ T cells were sensitized to inhaled OVA using the indicated adjuvants. Lung-draining LNs were excised 4 days later, cells from them were restimulated ex vivo with OVA, and the indicated cytokines in the culture supernatants were measured. Shown are cytokines from LN cultures of WT and Tlr4–/– mice sensitized to OVA using rmTNF as an adjuvant (n = 5 mice per group) (A), WT and TNFR1/2-DKO mice sensitized to OVA using either LPS or ASP as an adjuvant (n = 6 mice per group) (B), and WT and TNFR1- and TNFR2-single-KO mice sensitized to OVA using LPS as an adjuvant (n = 12 mice per group) (C). Data represent mean ± SEM from a single experiment, representative of 2, except C, which shows the combined data of 2 experiments yielding similar results. *P < 0.05, **P < 0.01, ***P < 0.001 for indicated comparisons (A) or WT vs. KO mice that were similarly treated (B and C); Kruskal-Wallis 1-way ANOVA with Dunn’s multiple comparison test.