Department of Immunology, University of Connecticut Health School of Medicine, Farmington, CT, USA.
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
Nat Immunol. 2021 Feb;22(2):154-165. doi: 10.1038/s41590-020-00844-7. Epub 2021 Jan 4.
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.
炎症性半胱天冬酶对细胞质脂多糖（LPS）的感应会触发细胞焦亡和同时释放损伤相关分子模式（DAMPs）。总的来说，DAMPs 是决定炎症性细胞死亡后果的关键因素。然而，释放的单个 DAMPs 的身份和功能尚未得到很好的定义。我们的蛋白质组学研究表明，细胞质 LPS 感应会触发半乳糖凝集素-1（一种β-半乳糖苷结合凝集素）的释放。半乳糖凝集素-1 的释放是炎症性细胞死亡（包括坏死性凋亡）的共同特征。使用半乳糖凝集素-1 缺陷小鼠、重组半乳糖凝集素-1 和半乳糖凝集素-1 中和抗体的体内研究表明，半乳糖凝集素-1 促进炎症，并在 LPS 诱导的致死性中发挥有害作用。从机制上讲，半乳糖凝集素-1 抑制 CD45（Ptprc）是其在内毒素休克中不利作用的基础。最后，我们发现脓毒症患者血清中的半乳糖凝集素-1 增加。总的来说，我们发现半乳糖凝集素-1 是细胞质 LPS 感应后释放的一种真正的 DAMPs，这为炎症性细胞死亡的新结果提供了依据。
