Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response

Camille de Cevins; Laure Delage; Maxime Batignes; Quentin Riller; Marine Luka; Anne Remaury; Boris Sorin; Tinhinane Fali; Cécile Masson; Bénédicte Hoareau; Catherine Meunier; Mélanie Parisot; Mohammed Zarhrate; Brieuc P Pérot; Víctor García-Paredes; Francesco Carbone; Lou Galliot; Béatrice Nal; Philippe Pierre; Luc Canard; Charlotte Boussard; Etienne Crickx; Jean-Claude Guillemot; Brigitte Bader-Meunier; Alexandre Bélot; Pierre Quartier; Marie-Louise Frémond; Bénédicte Neven; Galina Boldina; Franck Augé; Fischer Alain; Michel Didier; Frédéric Rieux-Laucat; Mickaël M Ménager

doi:10.1016/j.xcrm.2023.101333

Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response

Cell Rep Med. 2023 Dec 19;4(12):101333. doi: 10.1016/j.xcrm.2023.101333.

Authors

Camille de Cevins¹, Laure Delage², Maxime Batignes³, Quentin Riller⁴, Marine Luka⁵, Anne Remaury⁶, Boris Sorin⁴, Tinhinane Fali³, Cécile Masson⁷, Bénédicte Hoareau⁸, Catherine Meunier⁶, Mélanie Parisot⁹, Mohammed Zarhrate⁹, Brieuc P Pérot³, Víctor García-Paredes³, Francesco Carbone⁵, Lou Galliot¹⁰, Béatrice Nal¹⁰, Philippe Pierre¹¹, Luc Canard⁶, Charlotte Boussard⁴, Etienne Crickx¹², Jean-Claude Guillemot⁶, Brigitte Bader-Meunier¹³, Alexandre Bélot¹⁴, Pierre Quartier¹³, Marie-Louise Frémond¹⁵, Bénédicte Neven¹⁶, Galina Boldina¹⁷, Franck Augé¹⁷, Fischer Alain¹⁸, Michel Didier⁶, Frédéric Rieux-Laucat⁴, Mickaël M Ménager¹⁹

Affiliations

¹ Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France; Sanofi R&D Data and Data Science, Artificial Intelligence & Deep Analytics, Omics Data Science, 1 Av Pierre Brossolette, 91385 Chilly-Mazarin, France.
² Université de Paris Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France; Checkpoint Immunology, Immunology and Inflammation Therapeutic Area, Sanofi, 94400 Vitry-sur-Seine, France.
³ Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France.
⁴ Université de Paris Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
⁵ Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, 75015 Paris, France.
⁶ Genomics and Proteomics Groups, Translational Sciences, Sanofi R&D, 1 Av Pierre Brossolette, 91385 Chilly-Mazarin, France.
⁷ Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
⁸ Sorbonne Université, INSERM UMS037 PASS, Plateforme de Cytométrie (CyPS), Paris, France.
⁹ Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UAR3633, Paris Descartes Sorbonne Paris Cite University, Paris, France.
¹⁰ Aix Marseille Université, CNRS, INSERM, CIML, 13288 Marseille Cedex 9, France.
¹¹ Aix Marseille Université, CNRS, INSERM, CIML, 13288 Marseille Cedex 9, France; Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal; Shanghai Institute of Immunology, Department of Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
¹² Université de Paris Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France; Service de Médecine Interne, Centre national de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Fédération Hospitalo-Universitaire TRUE InnovaTive theRapy for immUne disordErs, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris Est Créteil, Créteil, France.
¹³ Pediatric Immuno-hematology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP. Centre Université Paris Cité, 75015 Paris, France.
¹⁴ International Center of Infectiology Research (CIRI), University of Lyon, INSERM U1111, Claude Bernard University, Lyon 1, CNRS, UMR5308, ENS of Lyon, Lyon, France; National Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE), Pediatric Nephrology, Rheumatology, Dermatology Unit, Hospital of Mother and Child, Hospices Civils of Lyon, Lyon, France.
¹⁵ Pediatric Immuno-hematology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP. Centre Université Paris Cité, 75015 Paris, France; Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, 75015 Paris, France.
¹⁶ Université de Paris Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France; Pediatric Immuno-hematology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP. Centre Université Paris Cité, 75015 Paris, France.
¹⁷ Sanofi R&D Data and Data Science, Artificial Intelligence & Deep Analytics, Omics Data Science, 1 Av Pierre Brossolette, 91385 Chilly-Mazarin, France.
¹⁸ Université de Paris, Imagine Institute, INSERM UMR 1163, 75015 Paris, France; Collège de France, Paris, France; Department of Paediatric Immuno-Haematology and Rheumatology, Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (AP-HP) 75015 Paris, France.
¹⁹ Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, 75015 Paris, France. Electronic address: mickael.menager@institutimagine.org.

Abstract

Gain-of-function mutations in stimulator of interferon gene 1 (STING1) result in STING-associated vasculopathy with onset in infancy (SAVI), a severe autoinflammatory disease. Although elevated type I interferon (IFN) production is thought to be the leading cause of the symptoms observed in patients, STING can induce a set of pathways, which have roles in the onset and severity of SAVI and remain to be elucidated. To this end, we performed a multi-omics comparative analysis of peripheral blood mononuclear cells (PBMCs) and plasma from SAVI patients and healthy controls, combined with a dataset of healthy PBMCs treated with IFN-β. Our data reveal a subset of disease-associated monocyte, expressing elevated CCL3, CCL4, and IL-6, as well as a strong integrated stress response, which we suggest is the result of direct PERK activation by STING. Cell-to-cell communication inference indicates that these monocytes lead to T cell early activation, resulting in their senescence and apoptosis. Last, we propose a transcriptomic signature of STING activation, independent of type I IFN response.

Keywords: SAVI; STING; integrated stress response; scRNA-seq; type I interferon; unfolded protein response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Interferon Type I* / metabolism
Leukocytes, Mononuclear / metabolism
Monocytes / metabolism
RNA
Vascular Diseases* / genetics
Vascular Diseases* / metabolism

Substances

Interferon Type I
RNA