1. Sepsis expands a CD39 + plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity
- Author
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Paulo Henrique Melo, Luisa Menezes-Silva, Fernando Q. Cunha, Marcos C. Borges, Bernhard Ryffel, Daniel Zoppi, Ícaro Maia Santos de Castro, Juliana E Toller-Kawahisa, Diego B. Caetite, Paula Ramos Viacava, Antonio Edson Rocha Oliveira, Raphael S. Peres, Helder I. Nakaya, Daniele C. Nascimento, Joel Linden, Thiago M. Cunha, Dario S. Zamboni, Gilles Kauffenstein, José C. Alves-Filho, Raphael Gomes Ferreira, Valérie F. J. Quesniaux, Denise Morais da Fonseca, Flávio P. Veras, Paula B. Donate, Annie R. Piñeros, Jonas Augusto Rizzato Paschoal, Marina Alves Damaceno, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
- Subjects
MACRÓFAGOS ,[SDV]Life Sciences [q-bio] ,Secondary infection ,medicine.medical_treatment ,Immunology ,Population ,Biology ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Macrophage ,education ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,B cells ,0303 health sciences ,education.field_of_study ,immunosuppression ,Immunosuppression ,medicine.disease ,Adenosine ,macrophages ,3. Good health ,Interleukin 10 ,Infectious Diseases ,adenosine ,030220 oncology & carcinogenesis ,plasmablast ,medicine.drug - Abstract
Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39hi B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39hi plasmablasts and adenosine accumulation. Our study reveals CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease.
- Published
- 2021
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