2. Academic Validation
  3. Intracellular immune sensing promotes inflammation via gasdermin D-driven release of a lectin alarmin

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

  • Nat Immunol. 2021 Feb;22(2):154-165. doi: 10.1038/s41590-020-00844-7.
Ashley J Russo 1,  Swathy O Vasudevan 1,  Santiago P Méndez-Huergo 2,  Puja Kumari 1,  Antoine Menoret 1 3,  Shivalee Duduskar 4,  Chengliang Wang 1,  Juan M Pérez Sáez 2,  Margaret M Fettis 5 6,  Chuan Li 1,  Renjie Liu 5,  Arun Wanchoo 5,  Karthik Chandiran 1,  Jianbin Ruan 1,  Sivapriya Kailasan Vanaja 1,  Michael Bauer 4 7,  Christoph Sponholz 7,  Gregory A Hudalla 5,  Anthony T Vella 1,  Beiyan Zhou 1,  Sachin D Deshmukh 4,  Gabriel A Rabinovich 2 8,  Vijay A Rathinam 9
Affiliations

Affiliations

  • 1 Department of Immunology, University of Connecticut Health School of Medicine, Farmington, CT, USA.
  • 2 Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
  • 3 Institute for Systems Genomics, University of Connecticut Health, Farmington, CT, USA.
  • 4 Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
  • 5 Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
  • 6 AbbVie Bioresearch Center, Worcester, MA, USA.
  • 7 Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany.
  • 8 Faculty of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina.
  • 9 Department of Immunology, University of Connecticut Health School of Medicine, Farmington, CT, USA. Rathinam@uchc.edu.
PMID: 33398185 DOI: 10.1038/s41590-020-00844-7
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.

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