Group 2 innate lymphoid cells exhibit progressively higher levels of activation during worsening of liver fibrosis

Abstract

Introduction: The interleukin-33/interleukin-13 pathway is involved in the immunopathology of liver fibrosis and recently characterized group 2 innate lymphoid cells (ILC2) were identified as profibrotic immune cells in the liver of mouse models. Our aim was to elucidate whether ILC2 might be present in human liver tissue and whether ILC2 contribute to liver fibrosis.

Materials and methods: To identify ILC2 in liver tissue and blood, we purified mononuclear immune cells from needle biopsies, cirrhotic explant specimen, and paired peripheral blood samples. Cell suspensions were incubated with specific markers for ILC2 and analyzed by flow cytometry. The CD69 marker was included to assess the activation level of ILC2. In addition, we determined the IL-33 plasma level.

Results: Results were correlated with the METAVIR fibrotic score of patients enrolled in this study. We detected ILC2 in a higher percentage of CD45⁺ cells in liver tissue than in paired peripheral blood. The number of ILC2 was significantly increased in fibrotic tissue, but only slightly increased in paired peripheral blood. A higher percentage of CD69⁺ ILC2 was observed in fibrotic tissue, and this increase correlates positively with aggravation of liver fibrosis measured by fibrotic METAVIR score. A higher level of plasma IL-33 was only detected in samples obtained from cirrhotic patients.

Conclusion: Our study indicates that ILC2 are present in the human liver and are activated in tissue contributing to the immunopathology of human liver fibrosis, independently of the etiology; which might be a potential new therapeutic target.

Keywords: Autoimmune hepatitis; ILC2; Liver disease; Steatohepatitis; Viral hepatitis.