Multi-omics: Differential expression of IFN-γ results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases

Authors

Heekyong R. Bae, National Cancer Institute at FrederickFollow
Patrick S.C. Leung, University of California, DavisFollow
Deborah L. Hodge, National Cancer Institute at FrederickFollow
John M. Fenimore, National Cancer Institute at FrederickFollow
Seon Min Jeon, Kyungpook National UniversityFollow
Vishal Thovarai, National Cancer Institute at FrederickFollow
Amiran Dzutsev, National Cancer Institute at FrederickFollow
Andrew A. Welcher, Amgen IncorporatedFollow
Michael Boedigheimer, Amgen IncorporatedFollow
Michael A. Damore, Amgen IncorporatedFollow
Myung Sook Choi, Kyungpook National UniversityFollow
Richard A. Fravell, Yale School of MedicineFollow
Giorgio Trinchieri, National Cancer Institute at FrederickFollow
M. Eric Gershwin, University of California, DavisFollow
Howard A. Young, National Cancer Institute at FrederickFollow

Date of this Version

7-1-2020

Citation

Journal of Autoimmunity 111 (2020) 102436

https://doi.org/10.1016/j.jaut.2020.102436

Comments

U.S. government work

Abstract

Low grade, chronic inflammation is a critical risk factor for immunologic dysfunction including autoimmune diseases. However, the multiplicity of complex mechanisms and lack of relevant murine models limit our understanding of the precise role of chronic inflammation. To address these hurdles, we took advantage of multi-omics data and a unique murine model with a low but chronic expression of IFN-γ, generated by replacement of the AU-rich element (ARE) in the 3’ UTR region of IFN-γ mRNA with random nucleotides. Herein, we demonstrate that low but differential expression of IFN-γ in mice by homozygous or heterozygous ARE replacement triggers distinctive gut microbial alterations, of which alteration is female-biased with autoimmune-associated microbiota. Metabolomics data indicates that gut microbiota-dependent metabolites have more robust sex-differences than microbiome profiling, particularly those involved in fatty acid oxidation and nuclear receptor signaling. More importantly, homozygous ARE-Del mice have dramatic changes in tryptophan metabolism, bile acid and long-chain lipid metabolism, which interact with gut microbiota and nuclear receptor signaling similarly with sex-dependent metabolites. Consistent with these findings, nuclear receptor signaling, encompassing molecules such as PPARs, FXR, and LXRs, was detectable as a top canonical pathway in comparison of blood and tissue-specific gene expression between female homozygous vs heterozygous ARE-Del mice. Further analysis implies that dysregulated autophagy in macrophages is critical for breaking self-tolerance and gut homeostasis, while pathways interact with nuclear receptor signaling to regulate inflammatory responses. Overall, pathway-based integration of multi-omics data provides systemic and cellular insights about how chronic inflammation driven by IFN-γ results in the development of autoimmune diseases with specific etiopathological features.