Indirect regulation of HMGB1 release by gasdermin D

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Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry

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Identified Weaknesses

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Paper Summary

Paperzilla title

HMGB1's Great Escape: Not Through the GSDMD Door, But Through the Bigger Hole!

This study found that HMGB1 release from macrophages following inflammasome activation isn't through GSDMD pores as previously thought, but rather due to cell lysis. In an endotoxemia mouse model, HMGB1 release was independent of GSDMD, suggesting different pathways for these molecules in vivo.

Possible Conflicts of Interest

None identified

Identified Weaknesses

Limited in vivo validation

The study primarily relies on in vitro experiments using bone marrow-derived macrophages (BMDMs), which may not fully reflect the complex in vivo environment. The in vivo model used (LPS injection) also has limitations as it primarily reflects a hepatocyte response and may not capture the full spectrum of immune cell involvement.

Potential off-target effects of interventions

The authors use various methods to activate or inhibit pyroptosis, some of which have off-target effects and could confound the results. For example, glycine, used to prevent pyroptosis, may have broader effects on cellular processes beyond inflammasome activation.

Incomplete assessment of alternative pathways

The study does not completely rule out other HMGB1 release pathways, particularly in vivo. Further investigation is needed to comprehensively evaluate the relative contributions of different pathways in various contexts.

Rating Explanation

This study offers valuable insights into the mechanism of HMGB1 release, challenging the prevailing view of its dependence on GSDMD pores. The experiments are well-designed and the conclusions are supported by the data. However, the limitations regarding in vivo validation and potential off-target effects prevent a rating of 5.

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Topic Hierarchy

Domain:

Life Sciences

Field:

Biochemistry, Genetics and Molecular Biology

Subfield:

Clinical Biochemistry

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Indirect regulation of HMGB1 release by gasdermin D

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