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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from Instituto de Salud Carlos III (ISCIII) and Fondos FEDER to ELC (PIE 15/00065, PI 18/00148, PI 14/01234) and to PP (20859/PI/18) and received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowaska-Curie grant agreement to KMH (No. 713673; La Caixa). CdF was supported by AECC Foundation (INVES192DELF). The Vall d Hebron University Hospital and Vall d Hebron Research Institute were supported by Plan Nacional de I+D+i 2013 to 2016 and Instituto de Salud Carlos III and Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003) cofinanced by European Development Regional Fund A way to achieve Europe, and by the European Union s Horizon 2020 Research and Innovation Program. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee (La Paz University Hospital, Madrid, PI-3761). Ethics Committee for Animal Experimentation of the Institutional Animal Care and Use Committee at Biomedical Research Institute (IIB, PI-2599). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data referred to in the manuscript are available.