Toll-Interacting Protein, Tollip, Inhibits IL-13-Mediated Pulmonary Eosinophilic Inflammation in Mice.

Abstract

Toll-interacting protein (Tollip) is a key negative regulator of innate immunity by preventing excessive proinflammatory responses. Tollip genetic variation has been associated with airflow limitation in asthma subjects and Tollip expression. Whether Tollip regulates lung inflammation in a type 2 cytokine milieu (e.g., IL-13) is unclear. Our goal was to determine the in vivo role of Tollip in IL-13-mediated lung eosinophilic inflammation and the underlying mechanisms. Tollip-knockout (KO) and wild-type (WT) mice were inoculated intranasally with recombinant mouse IL-13 protein to examine lung inflammation. To determine how Tollip regulates inflammation, alveolar macrophages and bone marrow-derived macrophages from Tollip KO and WT mice were cultured with or without IL-13 and/or IL-33. IL-13-treated Tollip KO mice significantly increased lung eosinophilic inflammation and eotaxin-2 (CCL24) levels compared with the WT mice. IL-13- treated Tollip KO (vs. WT) macrophages, in the absence and particularly in the presence of IL-33, increased expression of the IL-33 receptor ST2L and CCL24, which was in part dependent on enhanced activation of interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) and signal transducer and activator of transcription 6 (STAT6). Our results suggest that Tollip downregulates IL-13-mediated pulmonary eosinophilia in part through inhibiting the activity of the ST2L/IL-33/IRAK1 axis and STAT6.

• Authors: Yoko Ito, Niccolette Schaefer, Amelia Sanchez, David Francisco, Rafeul Alam, Richard J Martin, Julie G Ledford, Connor Stevenson, Di Jiang, Liwu Li, Monica Kraft, Hong Wei Chu
• Journal: Journal of innate immunity (J Innate Immun) Vol. 10 Issue 2 Pg. 106-118 ( 2018) ISSN: 1662-8128 [Electronic] Switzerland
• PMID: 29393212 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2018 S. Karger AG, Basel.

Chemical References

• Ccl24 protein, mouse
• Chemokine CCL24
• Interleukin-13
• Interleukin-33
• Intracellular Signaling Peptides and Proteins
• Receptors, Interleukin-1
• ST2L protein, mouse
• STAT6 Transcription Factor
• Stat6 protein, mouse
• Tollip protein, mouse
• Interleukin-1 Receptor-Associated Kinases
• Irak1 protein, mouse

Topics

• Animals
• Chemokine CCL24 (metabolism)
• Female
• Interleukin-1 Receptor-Associated Kinases (metabolism)
• Interleukin-13 (administration & dosage, immunology)
• Interleukin-33 (administration & dosage, immunology)
• Intracellular Signaling Peptides and Proteins (deficiency, immunology)
• Macrophages, Alveolar (immunology, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Pulmonary Eosinophilia (chemically induced, immunology, pathology)
• Receptors, Interleukin-1 (metabolism)
• STAT6 Transcription Factor (metabolism)
• Signal Transduction (immunology)