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The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling

Nature Medicine volume 17, pages 596–603 (2011)Cite this article

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Abstract

Individuals with chronic asthma show a progressive decline in lung function that is thought to be due to structural remodeling of the airways characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we show that the tumor necrosis factor (TNF) family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin β receptor (LTβR) reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung transforming growth factor-β (TGF-β) and interleukin-13 (IL-13), cytokines implicated in remodeling in humans, whereas exogenous administration of LIGHT to the airways induces fibrosis and smooth muscle hyperplasia, Thus, LIGHT may be targeted to prevent asthma-related airway remodeling.

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Figure 1: Blockade of LIGHT or LTαβ inhibits airway remodeling and AHR induced by HDM.
Figure 2: LIGHT-deficient mice are resistant to airway remodeling induced by HDM.
Figure 3: LIGHT controls lung TGF-β1 production and accumulation of LAP+ macrophages.
Figure 4: LTβR stimulation promotes fibrosis and TGF-β production by lung macrophages.
Figure 5: LIGHT-induced airway remodeling is in part dependent on TGF-β.
Figure 6: LIGHT promotes IL-13 production by lung eosinophils.

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Acknowledgements

We thank A. Meilan, Y. Adams, X. Tang and M. Macauley for technical assistance and the UCSD histology core for lung section processing and staining. Antibody to LTβ BBF6 was kindly provided by J. Browning, Biogen Idec. This work was supported by US National Institutes of Health (NIH) grant AI070535 to M.C., a fellowship from the American Academy of Asthma, Allergy and Immunology, UCSD Clinical and Translational Research Institute and NIH grant 1K08AI080938-01A1 award to T.A.D. and NIH grants R37AI068033 and AI067890 to C.F.W. This is manuscript number 1285 of the La Jolla Institute for Allergy and Immunology.

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  1. Taylor A Doherty and Pejman Soroosh: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA

    Taylor A Doherty, Pejman Soroosh, Satoshi Fukuyama, Heonsik Choi & Michael Croft

  2. Department of Medicine, University of California–San Diego (UCSD), La Jolla, California, USA

    Taylor A Doherty, Naseem Khorram, Peter Rosenthal, Jae Youn Cho, Bruce L Zuraw & David H Broide

  3. Institute of Medical Microbiology, Universität Düsseldorf, Düsseldorf, Germany

    Stefanie Scheu & Klaus Pfeffer

  4. Infectious and Inflammatory Diseases Center, Sanford Burnham Medical Research Institute, La Jolla, California, USA

    Paula S Norris & Carl F Ware

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Contributions

T.A.D. and P.S. contributed to animal antigen administration, surgery, data collection, analysis and manuscript writing for all studies; S.F. and J.Y.C. contributed to immunostaining and data analysis; N.K. contributed to remodeling and cytokine data collection and analysis; P.R. contributed to airway hyper-responsiveness testing and analysis; P.S.N. produced plasmids, LTβR-F and antibody to LTβR and contributed to experimental design; H.C. contributed to cytokine data collection; S.S. and K.P. developed mutant mice; B.L.Z. contributed to experimental design; C.F.W. contributed to experimental design and reagent production; D.H.B. contributed to experimental design and remodeling data collection; M.C. contributed to experimental design, data analysis and manuscript writing for all studies.

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Correspondence to Michael Croft.

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Doherty, T., Soroosh, P., Khorram, N. et al. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nat Med 17, 596–603 (2011). https://doi.org/10.1038/nm.2356

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