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DOI: 10.1055/s-0037-1612852
IL-33 regulates immune-mediated hepatitis by induction of M2 macrophages and ST2 Tregs
Publication History
Publication Date:
03 January 2018 (online)
Question:
Autoimmune hepatitis (AIH) is a chronic inflammatory disease characterized by ongoing tissue destruction mediated by autoreactive T cells that leads to necroinflammation. Interleukin (IL)-33, the most recently identified member of the IL-1 cytokine family plays a crucial role in intrahepatic immunity. IL-33 functions as an alarmin that is rapidly released from necrotic hepatocytes and leads to activation of immune cells, such as type 2 innate lymphoid cells and Tregs, by binding to its receptor ST2. In addition, IL-33 drives polarization of anti-inflammatory M2 macrophages. Although it was recently shown that IL-33 dampens immune-mediated liver injury, the exact mechanism remains ill defined.
Methods:
C57Bl/6 mice and ST2-/- mice were treated with IL-33 for up to four times on consecutive days. Thereafter, mice received Con A and were analyzed 24h later. Immune cell analysis was done by flow cytometry. FACS-sorted macrophage subsets were analyzed by quantitative RT-PCR.
Results:
C57BL/6 mice that received IL-33 before Con A application were protected from immune-mediated hepatitis, as shown by significantly reduced ALT values. Analysis of hepatic immune cells showed increased frequencies of eosinophilic granulocytes, macrophages, and Tregs upon IL-33 treatment. However, eosinophils were un-activated as shown by downregulation of activation markers CD69, CD62L and CD25. F4/80/CD11b macrophages in IL-33/Con A treated mice increased in frequency and had a Ly6clo/CD11c-/CX3CR1 phenotype. These cells expressed the typically M2 associated markers Arg-1, Ym-1 and Areg, suggesting an anti-inflammatory phenotype. Macrophage frequencies were also increased in mice that were treated with Con A, however these cells had a Ly6chi/CD11c phenotype, suggesting to be inflammatory M1 macrophages. Hepatic Tregs from IL-33/Con A-treated mice and Con A-treated mice showed increased expression of ST2. Yet, frequencies of ST2 Tregs from IL-33/Con A-treated mice were significantly higher. To specify the immunomodulatory effect of IL-33 during immune-mediated hepatitis, mice devoid of ST2 were used for further studies. These mice developed a more severe hepatitis associated with increased frequencies of activated eosinophils and inflammatory macrophages. Interestingly, the frequency of hepatic Tregs was increased compared to Con A-treated C57BL/6 mice, suggesting that the lack of ST2 Tregs causes the severity of hepatitis in ST2-/- mice.
Conclusions:
IL-33 functions as an immunomodulatory molecule that polarizes anti-inflammatory macrophages and activates Tregs in an ST2-dependent manner that mediate protection from immune-mediated hepatitis.
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