1886-P: Hepatic Type 2 Innate Lymphoid Cells Suppress Gluconeogenesis via the IL-33/GATA3/IL-13 Axis

Abstract

Type 2 innate lymphoid cells (ILC2s) were recently identified as essential components of innate immunity. Besides, beneficial roles of ILC2s in metabolic diseases are attracting attentions. Although the liver contains various immune cells including T cells and ILC2s, little is known about ILC2s in hepatic gluconeogenesis. We therefore investigated the role of ILC2s and the effect of IL-33, a potent ILC2 activator, on hepatic gluconeogenesis in mice. We found that recombinant IL-33 injection decreased fasting blood glucose levels in wild type mice. This effect was not observed in NOD/SCID Il2rg null (NSG) mice lacking certain immune cells including ILC2s, whereas the similar response was seen in another immune deficient mice Foxnnu/nu (nude mice), which have normal development in ILC2s. IL-33 treatment also suppressed hepatic gluconeogenesis assessed by pyruvate tolerance test in wt mice, while there was no response in NSG. Moreover, ILC2 transplantation was able to rescue the absence of glucose response by IL-33 in NSG. We observed a marked increase of IL-13+ ILC2 population in liver after IL-33 treatment, and Il13-/- mice did not show the decrease of blood glucose or the suppression of gluconeogenesis by IL-33 treatment. Additionally, the transfer of Il13-/- ILC2 failed to gain IL-33 induced glucose response in NSG, suggesting that the hypoglycemic effect of IL-33/ILC2s depends on IL-13. In consistent with these results, the differentially expressed gene analysis revealed that IL-13 treatment mostly altered the gene expressions of glucose metabolic process in primary hepatocytes. Notably, we identified GATA3 as a direct regulator of the effecter molecules such as Il5, Il13 and I1rl1 in hepatic ILC2s. These phenomena were also reproducible in human ILC2s and primary hepatocyte. In conclusion, these findings indicate that hepatic ILC2s suppress hepatic gluconeogenesis via the IL-33/GATA3/IL-13 axis, thus reducing blood glucose levels. Disclosure M. Fujimoto: None. K. Yokote: None. T. Tanaka: None.