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The Role of the IL-33/ST2 Axis in CpG-Induced Macrophage Activation Syndrome
Yuanji Dong1,2, Rongfen Gao1, Kailin He1
1Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Background:
Macrophage activation syndrome (MAS) is a fatal inflammatory condition, which is often associated with the elevation of multiple proinflammatory cytokines and multiple organ dysfunction. Previous studies have shown that ST2 contributes to T cell overactivation and plays a detrimental role in mouse models of primary hemophagocytic lymphohistiocytosis. The purpose of this study was to investigate the role of the IL-33/ST2 axis in a mouse model of MAS induced by repeated injections of cytosine-phosphate-guanine (CpG).
Methods:
Serum cytokines were determined using the cytometric bead array by flow cytometry. IL-33 and ST2 were detected by immunohistochemistry and real-time quantitative PCR in the liver and spleen of mice. CD3 and F4/80 in the liver were detected by immunohistochemistry. Inflammatory macrophages and effector memory T lymphocytes were detected by flow cytometry.
Result:
The CpG-induced MAS model was successfully induced after repeated CpG injections, presenting with hypercytokinemia and hepatosplenomegaly. The numbers of IL-33 positive cells in the liver and spleen decreased significantly, while the expression of ST2 in the liver tended to increase in the mice with MAS. IL-33 and St2 knockout mice showed similar levels of hepatosplenomegaly, peripheral blood count, and cytokine storm when compared with wild-type (WT) mice after induction of MAS. There were also no significant differences in liver pathology (including inflammatory cell infiltration of CD3 and F4/80) and levels of splenic inflammatory macrophages and effector memory T cells between the WT and knockout mice.
Conclusion:
These results suggested that IL-33 decreased in the liver and spleen tissues of MAS mice. Further results suggest that IL-33 and St2 knockout mice have no treatment potential in CpG-induced MAS. Thus, the IL-33/ST2 axis has little effect on the prognosis of CpG-induced MAS.
Insights
The IL-33/ST2 axis does not significantly impact macrophage activation syndrome (MAS) in mice. Knocking out IL-33 or ST2 did not alter disease severity, suggesting this pathway is not a viable therapeutic target for MAS.
Area of Science:
- Immunology
- Inflammation Biology
Background:
- Macrophage activation syndrome (MAS) is a severe, fatal inflammatory condition characterized by high cytokine levels and organ dysfunction.
- Previous research indicated ST2's detrimental role in T cell overactivation within hemophagocytic lymphohistiocytosis models.
- The IL-33/ST2 axis's involvement in MAS pathogenesis remained largely unexplored.
Purpose of the Study:
- To investigate the role of the IL-33/ST2 signaling pathway in a mouse model of MAS.
- To determine if the IL-33/ST2 axis influences the development and severity of CpG-induced MAS.
Main Methods:
- A mouse model of MAS was induced using repeated injections of cytosine-phosphate-guanine (CpG).
- IL-33 and ST2 expression levels were assessed in liver and spleen tissues via immunohistochemistry and qPCR.
- Cytokine levels, organomegaly, and immune cell populations (macrophages, T lymphocytes) were quantified in wild-type and IL-33/ST2 knockout mice.
Main Results:
- CpG injections successfully induced MAS, characterized by hypercytokinemia and hepatosplenomegaly.
- A significant decrease in IL-33 positive cells was observed in MAS mouse tissues, while ST2 expression showed an increasing trend.
- IL-33 and ST2 knockout mice exhibited comparable MAS severity, including cytokine storm, organomegaly, and immune cell profiles, to wild-type controls.
Conclusions:
- The IL-33/ST2 axis appears to have a minimal role in the pathogenesis of CpG-induced MAS.
- Targeting the IL-33/ST2 pathway does not offer therapeutic potential for MAS.
- Further research may be needed to identify other key pathways involved in MAS progression.
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