The prognostic impact of SIGLEC5-induced impairment of CD8+ T cell activation in sepsisResearch in context
Roberto Lozano-Rodríguez,
José Avendaño-Ortíz,
Karla Montalbán-Hernández,
Juan Carlos Ruiz-Rodríguez,
Ricardo Ferrer,
Alejandro Martín-Quirós,
Charbel Maroun-Eid,
Juan José González-López,
Anna Fàbrega,
Verónica Terrón-Arcos,
María Gutiérrez-Fernández,
Elisa Alonso-López,
Carolina Cubillos-Zapata,
María Fernández-Velasco,
Rebeca Pérez de Diego,
Pablo Pelegrin,
Carlos García-Palenciano,
Francisco J. Cueto,
Carlos del Fresno,
Eduardo López-Collazo
Affiliations
Roberto Lozano-Rodríguez
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
José Avendaño-Ortíz
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; CIBER of Respiratory Diseases (CIBERES), Avenida de Monforte de Lemos, 3-5, Madrid 28029, Spain
Karla Montalbán-Hernández
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
Juan Carlos Ruiz-Rodríguez
Intensive Care Department, Vall d'Hebron University Hospital, Organ Dysfunction and Resuscitation Research Group, Vall d'Hebron Institute of Research and Medicine Department, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119, Barcelona 08035, Spain
Ricardo Ferrer
Intensive Care Department, Vall d'Hebron University Hospital, Organ Dysfunction and Resuscitation Research Group, Vall d'Hebron Institute of Research and Medicine Department, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119, Barcelona 08035, Spain
Alejandro Martín-Quirós
Emergency Department, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
Charbel Maroun-Eid
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; Emergency Department, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
Juan José González-López
Microbiology Department, Vall d'Hebron University Hospital and Departament de Genètica i Microbiologia, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119, Barcelona 08035, Spain
Anna Fàbrega
Microbiology Department, Vall d'Hebron University Hospital and Faculty of Health Sciences, University of Vic – Central University of Catalonia (UVic-UCC), Manresa, Spain
Verónica Terrón-Arcos
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
María Gutiérrez-Fernández
Department of Neurology and Stroke Centre, Neuroscience and Cerebrovascular Research Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
Elisa Alonso-López
Department of Neurology and Stroke Centre, Neuroscience and Cerebrovascular Research Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
Carolina Cubillos-Zapata
CIBER of Respiratory Diseases (CIBERES), Avenida de Monforte de Lemos, 3-5, Madrid 28029, Spain
María Fernández-Velasco
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
Rebeca Pérez de Diego
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
Pablo Pelegrin
Biomedical Research Institute of Murcia (IMIB-Arrixaca), CIBERehd, Clinical University Hospital Virgen de la Arrixaca, Ctra. Madrid-Cartagena, s/n, El Palmar, Murcia 30120, Spain
Carlos García-Palenciano
Biomedical Research Institute of Murcia (IMIB-Arrixaca), CIBERehd, Clinical University Hospital Virgen de la Arrixaca, Ctra. Madrid-Cartagena, s/n, El Palmar, Murcia 30120, Spain
Francisco J. Cueto
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
Carlos del Fresno
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain
Eduardo López-Collazo
The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain; CIBER of Respiratory Diseases (CIBERES), Avenida de Monforte de Lemos, 3-5, Madrid 28029, Spain; Corresponding author. The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain.
Summary: Background: Sepsis is associated with T-cell exhaustion, which significantly reduces patient outcomes. Therefore, targeting of immune checkpoints (ICs) is deemed necessary for effective sepsis management. Here, we evaluated the role of SIGLEC5 as an IC ligand and explored its potential as a biomarker for sepsis. Methods: In vitro and in vivo assays were conducted to both analyse SIGLEC5's role as an IC ligand, as well as assess its impact on survival in sepsis. A multicentre prospective cohort study was conducted to evaluate the plasmatic soluble SIGLEC5 (sSIGLEC5) as a mortality predictor in the first 60 days after admission in sepsis patients. Recruitment included sepsis patients (n = 346), controls with systemic inflammatory response syndrome (n = 80), aneurism (n = 11), stroke (n = 16), and healthy volunteers (HVs, n = 100). Findings: SIGLEC5 expression on monocytes was increased by HIF1α and was higher in septic patients than in healthy volunteers after ex vivo LPS challenge. Furthermore, SIGLEC5-PSGL1 interaction inhibited CD8+ T-cell proliferation. Administration of sSIGLEC5r (0.8 mg/kg) had adverse effects in mouse endotoxemia models. Additionally, plasma sSIGLEC5 levels of septic patients were higher than HVs and ROC analysis revealed it as a mortality marker with an AUC of 0.713 (95% CI, 0.656–0.769; p < 0.0001). Kaplan–Meier survival curve showed a significant decrease in survival above the calculated cut-off (HR of 3.418, 95% CI, 2.380–4.907, p < 0.0001 by log-rank test) estimated by Youden Index (523.6 ng/mL). Interpretation: SIGLEC5 displays the hallmarks of an IC ligand, and plasma levels of sSIGLEC5 have been linked with increased mortality in septic patients. Funding: Instituto de Salud Carlos III (ISCIII) and “Fondos FEDER” to ELC (PIE15/00065, PI18/00148, PI14/01234, PI21/00869), CDF (PI21/01178), RLR (FI19/00334) and JAO (CD21/00059).
