1. Intracellular immune sensing promotes inflammation via gasdermin D-driven release of a lectin alarmin.
- Author
-
Russo AJ, Vasudevan SO, Méndez-Huergo SP, Kumari P, Menoret A, Duduskar S, Wang C, Pérez Sáez JM, Fettis MM, Li C, Liu R, Wanchoo A, Chandiran K, Ruan J, Vanaja SK, Bauer M, Sponholz C, Hudalla GA, Vella AT, Zhou B, Deshmukh SD, Rabinovich GA, and Rathinam VA
- Subjects
- Adult, Aged, Aged, 80 and over, Alarmins deficiency, Alarmins genetics, Animals, Case-Control Studies, Disease Models, Animal, Endotoxemia chemically induced, Endotoxemia metabolism, Endotoxemia pathology, Female, Galectin 1 blood, Galectin 1 deficiency, Galectin 1 genetics, HeLa Cells, Humans, Inflammation chemically induced, Inflammation metabolism, Inflammation pathology, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Leukocyte Common Antigens metabolism, Lipopolysaccharides, Macrophages immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Necroptosis, Phosphate-Binding Proteins deficiency, Phosphate-Binding Proteins genetics, RAW 264.7 Cells, Sepsis blood, Sepsis diagnosis, Signal Transduction, Up-Regulation, Alarmins metabolism, Endotoxemia immunology, Galectin 1 metabolism, Inflammation immunology, Inflammation Mediators metabolism, Intracellular Signaling Peptides and Proteins metabolism, Macrophages metabolism, Phosphate-Binding Proteins metabolism
- Abstract
Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs released are poorly defined. Our proteomics study revealed that cytosolic LPS sensing triggered the release of galectin-1, a β-galactoside-binding lectin. Galectin-1 release is a common feature of inflammatory cell death, including necroptosis. In vivo studies using galectin-1-deficient mice, recombinant galectin-1 and galectin-1-neutralizing antibody showed that galectin-1 promotes inflammation and plays a detrimental role in LPS-induced lethality. Mechanistically, galectin-1 inhibition of CD45 (Ptprc) underlies its unfavorable role in endotoxin shock. Finally, we found increased galectin-1 in sera from human patients with sepsis. Overall, we uncovered galectin-1 as a bona fide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.
- Published
- 2021
- Full Text
- View/download PDF