SIGLEC5: An immune checkpoint ligand in sepsis.

Sepsis is a global health priority. Despite thorough studies in mice models, its molecular and cellular basis remain unclear and there is no pharmacological effective treatment other than antimicrobial and supportive therapy. During sepsis, T cells exhaustion compromises patients outcome, and immune checkpoints (ICs) become crucial players in disease management. Here, a total of 425 patients with systemic inflammatory response criteria and 127 controls were studied. Soluble SIGLEC5 (sSIGLEC5) levels in plasma were higher in patients with sepsis compared to the other groups and even higher in those patients with septic-shock. sSIGLEC5 plasma levels were higher in non-survivors than in survivors and ROC curves analysis revealed sSIGLEC5 as a survival marker (cut-off ≤ 523.6 ng/mL). In vitro experiments illustrated how SIGLEC5 impaired CD8+ proliferation through binding to PSGL1. Blocking the SIGLEC5/PSGL1 axis reverted the latter effect. Mechanistically, SIGLEC5 overexpression was driven by HIF1α. Exogenous sSIGLEC5 accelerated death and magnified acute lung injury in mice models. Our data demonstrates how plasma sSIGLEC5 level on admission predicts death and stratifies patients with sepsis. This molecule exhibits the hallmarks of an IC ligand.