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

ASHLEY J. RUSSO; SWATHY O. VASUDEVAN; SANTIAGO MÉNDEZ HUERGO; PUJA KUMARI; ANTOINE MENORET; SHIVALEE DUDUSKAR; CHENGLIANG WANG; JUAN M. PÉREZ SÁEZ; MARGARET M. FETTIS; CHUAN LI; RENJIE LIU; ARUN WANCHOO; KARTHIK CHANDIRAN; JIANBIN RUAN; SIVAPRIYA KAILASAN VANAJA; MICHAEL BAUER; CHRISTOPH SPONHOLZ; GREGORY A. HUDALLA; ANTHONY T. VELLA; BEIYAN ZHOU; SACHIN D. DESHMUKH; GABRIEL A. RABINOVICH; VIJAY A. RATHINAM

NATURE IMMUNOLOGY (PRINT)

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2021 p. 154 - 165

1529-2908

Inflammatory caspase-sensing of cytosolic 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 revealed that cytosolic LPS sensing triggered the release of galectin-1, a β-galactoside-binding lectin. Galectin-1 release is found to be 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 lipopolysaccharide (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 septic patients. Overall, we uncovered galectin-1 as a bonafide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.