TIM-1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death

Background—Studies of asthma have been limited by a poor understanding of how non-allergic environmental exposures such as air pollution and infection are translated in the lung into inflammation and wheezing. Objective—Our goal was to understand the mechanism of non-allergic asthma that lead to airway hyperreactivity (AHR), a cardinal feature of asthma independent of adaptive immunity. Method—We examined mouse models of experimental asthma, in which AHR was induced by Respiratory Syncytial Virus (RSV) infection or ozone exposure, using mice deficient in TIM1/ HAVCR1, an important asthma susceptibility gene. Results—TIM1−/− mice failed to develop airways disease when infected with RSV or when repeatedly exposed to ozone, a major component of air pollution. On the other hand, the TIM1−/− mice developed allergen-induced experimental asthma, as previously shown. The RSVand ozone-induced pathways were blocked by treatment with caspase inhibitors, indicating an absolute requirement for programmed cell death and apoptosis. TIM-1-expressing, but not TIM-1-deficient, natural killer T (NKT) cells responded to apoptotic airway epithelial cells by secreting cytokines, which mediated the development of airway hyperreactivity. © 2013 American Academy of Allergy, Asthma and Immunology. Published by Mosby, Inc. All rights reserved. *To whom correspondence should be addressed: Dale T. Umetsu, MD, PhD, Division of Immunology, Karp Laboratories, Rm 10127, Children's Hospital, Harvard Medical School, One Blackfan Circle, Boston, MA 02115, USA. Phone: 617.919.2439, Fax: 617.730.0384, dale.umetsu@childrens.harvard.edu. 6Current address of this author is institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 7These authors contributed equally to the completion of these studies. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest: The authors have declared that no conflicts of interest exist. NIH Public Access Author Manuscript J Allergy Clin Immunol. Author manuscript; available in PMC 2014 August 01. Published in final edited form as: J Allergy Clin Immunol. 2013 August ; 132(2): 414–425.e6. doi:10.1016/j.jaci.2013.03.025. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript Conclusion—We defined a novel pathway in which TIM-1, a receptor for phosphatidylserine expressed by apoptotic cells, drives the development of asthma by sensing and responding to injured and apoptotic airway epithelial cells.