Intracellular immune sensing promotes inflammation via gasdermin D-driven release of a lectin alarmin

Area of Science:

• Immunology
• Cellular Biology
• Molecular Medicine

Background:

• Inflammatory caspases sense cytosolic lipopolysaccharide (LPS), initiating pyroptosis and releasing damage-associated molecular patterns (DAMPs).
• The specific DAMPs released and their functions following inflammatory cell death remain incompletely understood.

Purpose of the Study:

• To identify novel DAMPs released upon cytosolic LPS sensing.
• To elucidate the role of galectin-1 in inflammatory cell death, particularly in the context of LPS-induced inflammation and lethality.

Main Methods:

• Proteomics analysis to identify released proteins following cytosolic LPS sensing.
• In vivo studies using galectin-1-deficient mice, recombinant galectin-1, and neutralizing antibodies.
• Investigation of galectin-1's mechanism of action, including its interaction with CD45 (Ptprc).
• Analysis of galectin-1 levels in human sepsis patient sera.

Main Results:

• Proteomics identified galectin-1, a β-galactoside-binding lectin, as a DAMP released upon cytosolic LPS sensing.
• Galectin-1 release was observed in various inflammatory cell death forms, including necroptosis.
• Galectin-1 deficiency protected mice from LPS-induced lethality, while recombinant galectin-1 exacerbated it.
• Galectin-1 was found to inhibit CD45 (Ptprc), contributing to its detrimental effects in endotoxin shock.
• Elevated galectin-1 levels were detected in human sepsis patients' sera.

Conclusions:

• Galectin-1 is a newly identified DAMP released during inflammatory cell death triggered by cytosolic LPS.
• Galectin-1 plays a significant detrimental role in inflammation and lethality associated with LPS exposure.
• Inhibition of CD45 by galectin-1 is a key mechanism underlying its pathological effects in endotoxin shock.
• Increased serum galectin-1 in sepsis patients suggests its clinical relevance as a biomarker or therapeutic target.