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Long-term immune dysfunction induced by sepsis is dependent on age
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  • David Colón,
  • Carlos Wanderley,
  • Walter Turato,
  • Vanessa Borges,
  • Marcelo Franchin,
  • Fernanda Castanheira,
  • Daniele Nascimento,
  • Douglas Prado,
  • Mikhael Haruo,
  • Leila Volpon,
  • Silvia Kavaguti,
  • Ana P. Carlotti,
  • Fabio Carmona,
  • Bernardo Franklin,
  • Thiago Cunha,
  • Jose Alves-Filho,
  • Fernando Cunha
David Colón
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil.
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Carlos Wanderley
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil
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Walter Turato
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil.
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Vanessa Borges
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil
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Marcelo Franchin
School of Dentistry, Alfenas Federal University, Alfenas, Brazil.
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Fernanda Castanheira
University of Calgary
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Daniele Nascimento
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil.
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Douglas Prado
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil.
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Mikhael Haruo
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil
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Leila Volpon
Department of Pediatrics, University of São Paulo, Ribeirão Preto Brazil
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Silvia Kavaguti
Department of Pediatrics, University of São Paulo, Ribeirão Preto Brazil
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Ana P. Carlotti
Department of Pediatrics, University of São Paulo, Ribeirão Preto Brazil
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Fabio Carmona
Department of Pediatrics, University of São Paulo, Ribeirão Preto Brazil
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Bernardo Franklin
Institute of Innate Immunity, Medical Faculty, University of Bonn, Germany
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Thiago Cunha
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil
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Jose Alves-Filho
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil
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Fernando Cunha
Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Ribeirão Preto Brazil

Corresponding Author:[email protected]

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Abstract

Background and Purpose: Sepsis-surviving adult individuals commonly develop immunosuppression and increased susceptibility to secondary infections, outcome mediated by the axis IL-33/ILC2s/M2 macrophages/Tregs. Nonetheless, the long-term immune consequences of pediatric sepsis are indeterminate. We sought to investigate the role of age in the genesis of immunosuppression following sepsis. Experimental Approach: Here, we compared the frequency of Tregs, the activation of the IL33/ILC2s axis in M2 macrophages, and the DNA methylation of epithelial lung cells from post-septic infant and adult mice. Likewise, sepsis-surviving mice were inoculated intranasally with Pseudomonas aeruginosa or by subcutaneous inoculation of the B16 melanoma cell line. Finally, blood samples from sepsis-surviving patients were collected and the concentrations of IL-33 and Tregs frequency were assessed. Key Results: In contrast to 6-week-old, 2-week-old mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL-33 levels, Tregs expansion, and activation of ILC2s and M2-macrophages were observed in 6-week-old but not 2-week-old post-septic mice. Moreover, impaired IL-33 production in 2-week-old post-septic mice was associated with increased DNA methylation in lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in 2-week-old mice. Clinically, adults but not pediatric post-septic patients exhibited higher counts of Tregs and sera IL-33 levels. Conclusion and Implications: These findings demonstrate a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression. Thus, a better understanding of this process could lead to differential treatments for adult and pediatric sepsis.
26 Feb 2023Submitted to British Journal of Pharmacology
27 Feb 2023Submission Checks Completed
27 Feb 2023Assigned to Editor
27 Feb 2023Review(s) Completed, Editorial Evaluation Pending
04 Mar 2023Reviewer(s) Assigned
13 Apr 2023Editorial Decision: Revise Minor
14 Jul 20231st Revision Received
20 Jul 2023Submission Checks Completed
20 Jul 2023Assigned to Editor
20 Jul 2023Review(s) Completed, Editorial Evaluation Pending
17 Aug 2023Editorial Decision: Accept