Role for nuclear interleukin-37 in the suppression of innate immunity

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-03, Vol.116 (10), p.4456-4461
• Main Authors: Li, Suzhao, Amo-Aparicio, Jesus, Neff, Charles P., Tengesdal, Isak W., Azam, Tania, Palmer, Brent E., López-Vales, Rubén, Bufler, Philip, Dinarello, Charles A.
• Format: Article
• Language: English
• Subjects: Alanine; Amino acids; Animals; Aspartic acid; Biological Sciences; Caspase; Caspase-1; Cell activation; Cell Nucleus - metabolism; Cytokines; Cytokines - metabolism; Endotoxemia; Female; IL-1β; Immunity; Immunity, Innate - genetics; Inflammation; Innate immunity; Interleukin 1; Interleukin 6; Interleukin-1 - genetics; Interleukin-1 - physiology; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Liver; Lungs; Macrophages; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Male; MAP kinase; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; NF-kappa B - metabolism; NF-κB protein; Nuclear transport; Peritoneum; Protein Transport; Receptors; Rodents; Transgenic animals; Transgenic mice; Translocation; Tumor necrosis factor-α; γ-Interferon
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1821111116

The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1α and IL-33, IL-37 is a dual-function cytokine in that IL-37 translocates to the nucleus but also transmits a signal via surface membrane receptors. The role of nuclear IL-37 remains unknown on the ability of this cytokine to inhibit innate inflammation. Here, we compared suppression of innate inflammation in transgenic mice expressing native human IL-37 (IL-37Tg) with those of transgenic mice carrying the mutation of aspartic acid (D) to alanine (A) at amino acid 20 (IL-37D20ATg). The mutation D20A prevents cleavage of caspase-1, a step required for IL-37 nuclear translocation. In vitro, peritoneal macrophages from IL-37Tg mice reduced LPS-induced IL-1β, IL-6, TNFα and IFNγ by 40–50% whereas in macrophages from IL-37D20ATg mice this suppression was not observed, consistent with loss of nuclear function. Compared with macrophages from IL-37Tg mice, significantly less or no suppression of LPS-induced MAP kinase and NFκB activation was also observed in macrophages from IL-37D20ATg mice. In vivo, levels of IL-1β, IL-6, and TNFα in the lungs and liver were markedly reduced during endotoxemia in IL-37Tg mice but not observed in IL-37D20ATg mice. However, suppression of innate inflammation remains intact in the IL-37D20A mice once the cytokine is released from the cell and binds to its receptor. These studies reveal a nuclear function for suppression of innate inflammation and are consistent with the dual function of IL-37 and a role for caspase-1 in limiting inflammation.