Cyclic GMP-AMP Triggers Asthma in an IL-33-Dependent Manner That Is Blocked by Amlexanox, a TBK1 Inhibitor.

Abstract

Extracellular host-derived DNA, as one of damage associated molecular patterns (DAMPs), is associated with allergic type 2 immune responses. Immune recognition of such DNA generates the second messenger cyclic GMP-AMP (cGAMP) and induces type-2 immune responses; however, its role in allergic diseases, such as asthma, has not been fully elucidated. This study aimed to determine whether cGAMP could induce asthma when used as an adjuvant. We intranasally sensitized mice with cGAMP together with house dust mite antigen (HDM), followed by airway challenge with HDM. We then assessed the levels of eosinophils in the broncho-alveolar lavage fluid (BALF) and serum HDM-specific antibodies. cGAMP promoted HDM specific allergic asthma, characterized by significantly increased HDM specific IgG1 and total IgE in the serum and infiltration of eosinophils in the BALF. cGAMP stimulated lung fibroblast cells to produce IL-33 in vitro, and mice deficient for IL-33 or IL-33 receptor (ST2) failed to develop asthma enhancement by cGAMP. Not only Il-33-/- mice, but also Sting-/-, Tbk1-/-, and Irf3-/-Irf7-/- mice which lack the cGAMP-mediated innate immune activation failed to increase eosinophils in the BALF than that from wild type mice. Consistently, intranasal and oral administration of amlexanox, a TBK1 inhibitor, decreased cGAMP-induced lung allergic inflammation. Thus, cGAMP functions as a type 2 adjuvant in the lung and can promote allergic asthma in manners that dependent on the intracellular STING/TBK1/IRF3/7 signaling pathway and the resultant intercellular signaling pathway via IL-33 and ST2 might be a novel therapeutic target for allergic asthma.

• Authors: Koji Ozasa, Burcu Temizoz, Takato Kusakabe, Shingo Kobari, Masatoshi Momota, Cevayir Coban, Shuichi Ito, Kouji Kobiyama, Etsushi Kuroda, Ken J Ishii
• Journal: Frontiers in immunology (Front Immunol) Vol. 10 Pg. 2212 ( 2019) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 31616416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Ozasa, Temizoz, Kusakabe, Kobari, Momota, Coban, Ito, Kobiyama, Kuroda and Ishii.

Chemical References

• Allergens
• Aminopyridines
• Il33 protein, mouse
• Immunoglobulin G
• Interleukin-33
• Nucleotides, Cyclic
• cyclic guanosine monophosphate-adenosine monophosphate
• Immunoglobulin E
• amlexanox
• Tbk1 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Allergens (drug effects, immunology)
• Aminopyridines (pharmacology)
• Animals
• Asthma (drug therapy, immunology)
• Bronchoalveolar Lavage Fluid (immunology)
• Eosinophils (drug effects, immunology)
• Female
• Immunoglobulin E (immunology)
• Immunoglobulin G (immunology)
• Interleukin-33 (immunology)
• Lung (drug effects, immunology)
• Mice
• Mice, Inbred C57BL
• Nucleotides, Cyclic (immunology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, immunology)
• Pulmonary Eosinophilia (drug therapy, immunology)
• Pyroglyphidae (immunology)
• Signal Transduction (drug effects, immunology)