Sepsis expands a CD39(+) plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity

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Nascimento, Daniele Carvalho ^{[1, 2, 3]} ; Viacava, Paula Ramos ^{[1, 2]} ; Ferreira, Raphael Gomes ^{[1, 2]} ; Damaceno, Marina Alves ^[4] ; Pineros, Annie Rocio ^{[1, 2]} ; Melo, Paulo Henrique ^{[1, 2]} ; Donate, Paula Barbim ^{[1, 2]} ; Toller-Kawahisa, Juliana Escher ^{[1, 2]} ; Zoppi, Daniel ^[5] ; Veras, Flavio Protasio ^{[1, 2]} ; Peres, Raphael Sanches ^{[1, 2]} ; Menezes-Silva, Luisa ^[6] ; Caetite, Diego ^{[1, 2]} ; Rocha Oliveira, Antonio Edson ^[7] ; Santos Castro, Icaro Maia ^[7] ; Kauffenstein, Gilles ^[8] ; Nakaya, Helder Imoto ^[9] ; Borges, Marcos Carvalho ^[5] ; Zamboni, Dario Simoes ^{[10, 2]} ; Fonseca, Denise Morais ^[6] ; Rizzato Paschoal, Jonas Augusto ^[4] ; Cunha, Thiago Mattar ^{[1, 2]} ; Quesniaux, Valerie ^{[3, 11]} ; Linden, Joel ^[12] ; Cunha, Fernando Queiroz ^{[1, 2]} ; Ryffel, Bernhard ^{[3, 11]} ; Alves-Filho, Jose Carlos ^{[1, 2]}

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^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ctr Res Inflammatory Dis, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] CNRS, UMR7355, F-45071 Orleans - France

^[4] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Biomol Sci, BR-14049900 Ribeirao Preto, SP - Brazil

^[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, BR-14049900 Ribeirao Preto, SP - Brazil

^[6] Univ Sao Paulo, Inst Biomed Sci, BR-05508000 Sao Paulo, SP - Brazil

^[7] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508000 Sao Paulo, SP - Brazil

^[8] Univ Strasbourg, Regenerat NanoMed, UMR INSERM 1260, F-60026 Strasbourg - France

^[9] Hosp Israelita Albert Einstein, BR-05620900 Sao Paulo - Brazil

^[10] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cell Biol, BR-14049900 Ribeirao Preto, SP - Brazil

^[11] Univ Orleans, Expt & Mol Immunol & Neurogenet, F-45071 Orleans - France

^[12] Univ Virginia, Ctr Immun Inflammat & Regenerat Med, Div Nephrol, Sch Med, Charlottesville, VA 22903 - USA

• Tipo de documento: Artigo Científico
• Fonte: IMMUNITY; v. 54, n. 9, p. 2024+, SEP 14 2021.
• Citações Web of Science: 0

Resumo

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 CD39(hi) 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 CD39(hi) plasmablasts and adenosine accumulation. Our study reveals CD39(hi) plasmablasts and adenosine as important drivers of sepsisinduced immunosuppression with relevance in human disease. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 15/25974-3 - Papel da ectonucleotidase CD39 no estabelecimento da imunossupressão induzida pela sepse
• Beneficiário: Daniele Carvalho Bernardo Nascimento
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 12/10100-0 - O papel das ectonucleotidases e da adenosina no estabelecimento da imunossupressão induzida pela sepse
• Beneficiário: Daniele Carvalho Bernardo Nascimento
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/25364-0 - Cicatriz imunológica pós-infecção intestinal aguda e desenvolvimento de desordens metabólicas: estudo das interações entre a microbiota e sistema imunológico do mesentério
• Beneficiário: Denise Morais da Fonseca
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores