Interleukin-33 (IL-33) is a multifunctional cytokine that mediates local inflammation upon tissue damage. IL-33 is known to act on multiple cell types including group 2 innate lymphoid cells (ILC2s), Th2 cells, and mast cells to drive production of Th2 cytokines including IL-5 and IL-13. IL-33 signaling activity through transmembrane ST2L can be inhibited by soluble ST2 (sST2), which acts as a decoy receptor. Previous findings suggested that modulation of IL-13 levels in mice lacking decoy IL-13Rα2, or mice lacking IL-13, impacted responsiveness to IL-33. In this study, we used Il13-/- mice to investigate whether IL-13 regulates IL-33 activity by modulating the transmembrane and soluble forms of ST2. In Il13-/- mice, the effects of IL-33 administration were exacerbated relative to wild type (WT). Il13-/- mice administered IL-33 i.p. had heightened splenomegaly, more immune cells in the peritoneum including an expanded ST2L+ ILC2 population, increased eosinophilia in the spleen and peritoneum, and reduced sST2 in the circulation and peritoneum. In the spleen, lung, and liver of mice given IL-33, gene expression of both isoforms of ST2 was increased in Il13-/- mice relative to WT. Because IL-13 and IL-4 signal through a shared receptor complex IL-13Rα1/IL-4Rα, we also studied the combined deficiency of IL-4 and IL-13 using Il4rα-/- mice which are defective in both IL-4 and IL-13 signaling. Responses of Il4rα-/- mice were indistinguishable from those of Il13-/- mice in our model system of IL-33-induced inflammation, suggesting that IL-4 does not play a distinct role separate from IL-13 in regulation of IL-33 activity. Through in vitro experiments, we confirmed fibroblasts to be an IL-13-responsive cell type that can regulate IL-33 activity through production of sST2. This study elucidates the important regulatory activity that IL-13 exerts on IL-33 through induction of IL-33 decoy receptor sST2 and through modulation of ST2L+ ILC2s.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/45519 |
| Date | 25 January 2023 |
| Creators | Zhang, Melvin |
| Contributors | Kasaian, Marion T. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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