Modulation of Liver Inflammation and Fibrosis by Interleukin-37

• Published in: Frontiers in immunology Vol. 12; p. 603649
• Main Authors: Mountford, Steffeni, Effenberger, Maria, Noll-Puchta, Heidi, Griessmair, Lucas, Ringleb, Andrea, Haas, Sonja, Denk, Gerald, Reiter, Florian P, Mayr, Doris, Dinarello, Charles A, Tilg, Herbert, Bufler, Philip
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 04-03-2021
• Subjects: Animals; Disease Models, Animal; Hepatitis - genetics; Hepatitis - immunology; Hepatitis - pathology; Humans; IL-37; Immunology; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Interleukin-1 - genetics; Interleukin-1 - immunology; Kupffer Cells - immunology; Kupffer Cells - pathology; Liver Cirrhosis - genetics; Liver Cirrhosis - immunology; Liver Cirrhosis - pathology; liver inflammation; Mice; Mice, Knockout; serum levels; Smad3; TGF-β; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology; IL-37; TGF-β; Smad3; liver inflammation; serum levels
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.603649

Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-β. TGF-β promotes liver fibrosis
the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-β signaling cascade to modulate liver fibrogenesis.
The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity.
Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl
-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-β-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1β stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis.
Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis.