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Hyperinflammation: On the pathogenesis and treatment of macrophage activation syndrome
1Department of Women's and Children's Health, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden.
Abstract:
Macrophage activation syndrome (MAS) is a subtype of hemophagocytic lymphohistiocytosis (HLH) diseases. The underlying mechanism of these life-threatening disorders is impaired granule-mediated cytotoxicity exerted by natural killer (NK) cells and T lymphocytes. This function is meant for elimination of virus-infected cells, malignant cells and to prevent exaggerated immune responses. The normal outcome after an attack by NK or cytotoxic T cells is apoptosis of the target cell. This prevents cytotoxic inflammatory responses in adjacent tissues which occur after lytic cell death. Extensive cell lysis can even produce a cytokine storm, as evidenced in MAS. Programmed proinflammatory lytic cell death, pyroptosis, caused by activated inflammasomes is central in the pathogenesis of MAS. Pyroptosis mediates IL-18 cytokine release, which robustly stimulates NK and T cells to produce IFN-γ, the key macrophage-activating signal which initiates a burst of inflammatory cytokines and chemokines. Lytic cell death also mediates a discharge of the prototype alarmin high mobility group box protein 1 (HMGB1), a proinflammatory molecule present in all cells and that mediates the pathogenesis of MAS as outlined here. Therapeutic options to control causal factors operating in the pathogenesis of MAS are also discussed.
Insights
Macrophage activation syndrome (MAS), a type of hemophagocytic lymphohistiocytosis (HLH), involves impaired NK and T cell cytotoxicity. Pyroptosis and HMGB1 release drive MAS pathogenesis by promoting cytokine storms.
Area of Science:
- Immunology
- Pathology
Background:
- Macrophage activation syndrome (MAS) is a severe subtype of hemophagocytic lymphohistiocytosis (HLH).
- MAS pathogenesis involves impaired cytotoxicity of natural killer (NK) cells and T lymphocytes, crucial for eliminating infected or malignant cells and preventing immune overreactions.
- Normal cytotoxic responses lead to target cell apoptosis, preventing widespread inflammation; however, extensive cell lysis can trigger a cytokine storm, characteristic of MAS.
Purpose of the Study:
- To elucidate the central role of programmed inflammatory cell death, pyroptosis, in MAS pathogenesis.
- To highlight the contribution of IL-18 and IFN-γ signaling in MAS.
- To discuss the involvement of high mobility group box protein 1 (HMGB1) in MAS and potential therapeutic strategies.
Main Methods:
- The study focuses on the mechanisms of cell death and cytokine release in MAS.
- It examines the role of inflammasome activation leading to pyroptosis.
- It analyzes the signaling pathways involving IL-18, IFN-γ, and HMGB1.
Main Results:
- Pyroptosis, a programmed inflammatory lytic cell death pathway activated by inflammasomes, is central to MAS pathogenesis.
- Pyroptosis drives IL-18 release, which subsequently stimulates NK and T cells to produce IFN-γ, a key signal for macrophage activation.
- Lytic cell death also results in the release of HMGB1, a pro-inflammatory alarmin contributing to MAS pathogenesis.
Conclusions:
- Pyroptosis and subsequent cytokine release (IL-18, IFN-γ) are critical drivers of MAS.
- HMGB1 release during lytic cell death further exacerbates MAS pathogenesis.
- Understanding these mechanisms offers therapeutic targets for controlling MAS.
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