Characterization of immune responses and the lung transcriptome in a murine model of IL-33 challenge

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1866; no. 12; p. 165950
• Main Authors: Piyadasa, Hadeesha, Lloyd, Dylan, Lee, Amy H.Y., Altieri, Anthony, Hemshekhar, Mahadevappa, Osawa, Natasha, Basu, Sujata, Blimkie, Travis, Falsafi, Reza, Halayko, Andrew J., Hancock, Robert E.W., Mookherjee, Neeloffer
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2020
• Subjects: Administration, Intranasal; Airway inflammation; Animals; Female; IL-33; Interleukin-33 - administration & dosage; Interleukin-33 - immunology; Lung - immunology; Lung - metabolism; Lung - pathology; Lungs; Mice; Mice, Inbred BALB C; Models, Animal; RNA-Seq; STAT4; Transcriptome; STAT4; Airway inflammation; Lungs; IL-33; Transcriptome
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2020.165950

IL-33 induces airway inflammation and hyper-responsiveness in respiratory diseases. Although defined as a therapeutic target, there are limited studies that have comprehensively investigated IL-33-mediated responses in the lungs in vivo. In this study, we characterized immunological and physiological responses induced by intranasal IL-33 challenge, in a mouse model. We identified specific cytokines, IL-4, IL-5, IL-6, IL-10, IP-10 and MIP1-α, that are increased in bronchoalveolar lavage and lung tissues by IL-33. Using transcriptomics (RNA-Seq) we demonstrated that 2279 transcripts were up-regulated and 1378 downregulated (≥ 2-fold, p < 0.01) in lung tissues, in response to IL-33. Bioinformatic interrogation of the RNA-Seq data was used to predict biological pathways and upstream regulators involved in IL-33-mediated responses. We showed that the mRNA and protein of STAT4, a predicted upstream regulator of IL-33-induced transcripts, was significantly enhanced in the lungs following IL-33 challenge. Overall, this study provides specific IL-33-induced molecular targets and endpoints that can be used as a resource for in vivo studies, e.g. in preclinical murine models examining novel interventions to target downstream effects of IL-33. •IL-33 predominantly increases eosinophils and neutrophils in the lungs of mice.•Intranasal IL-33 challenge alters the lung transcriptome (detailed by RNA-Seq).•STAT4 is a predicted upstream regulator of IL-33-induced transcripts.•STAT4 transcript and protein are significantly enhanced in the lungs, following IL-33 challenge.