NOX2 decoy peptides disrupt trauma-mediated neutrophil immunosuppression and protect against lethal peritonitis
Trauma and sepsis are frequent causes of immunosuppression and risk of secondary bacterial infections and mortality among critically ill patients. Reduced activity of neutrophil NADPH oxidase 2 (NOX2) and impaired bacterial killing are among the major indices of immunosuppression. We hypothesize tha...
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Published in | Redox biology Vol. 36; p. 101651 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
Elsevier B.V
01.09.2020
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | Trauma and sepsis are frequent causes of immunosuppression and risk of secondary bacterial infections and mortality among critically ill patients. Reduced activity of neutrophil NADPH oxidase 2 (NOX2) and impaired bacterial killing are among the major indices of immunosuppression. We hypothesize that NOX2-decoy peptides disrupt the inhibition of neutrophil NOX2 by plasma of patients with severe trauma and immunosuppression, thereby preserving the neutrophil respiratory burst that is a central antimicrobial mechanism. We demonstrate that plasma from trauma/hemorrhage (T/H) patients, but not healthy donors (HD), significantly reduced the activity of neutrophil NOX2 and impaired bacterial killing. The inhibitory action of plasma was associated with an increase in bacterial infections among trauma survivors. High Mobility Group Box 1 (HMGB1) is a mediator of lethality in trauma and sepsis and our mechanistic studies revealed that disulfide and oxidized forms of HMGB1 bind to the gp91phox subunit of NOX2, and thus decrease the neutrophil respiratory burst and bacterial killing. NOX2 decoy Anti-Immunosuppression (Ai) Peptides 1 and 3 effectively disrupted the immunosuppressive action of T/H plasma. HMGB1 selectively binds to Ai-Peptide 3, supporting the possibility for direct interaction between HMGB1 and the third external loop of gp91phox. In vivo, Ai-Peptides improved survival of mice subjected to lethal peritonitis. Taken together, plasma-dependent inhibition of neutrophil NOX2 appeared to be a suitable indicator of immunosuppression in patients with severe trauma. Given that gp91phox decoys protected the neutrophil respiratory burst, selected Ai-Peptides have therapeutic potential to reduce bacterial infections and end-organ injury associated with sepsis/trauma-induced immunosuppression.
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•Plasma-induced neutrophil dysfunction is linked to immunosuppression in trauma.•HMGB1 are among relevant mediators of neutrophil immunosuppression.•NOX2 decoy peptides improved survival of mice with intraperitoneal infections. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors have equal contribution. |
ISSN: | 2213-2317 2213-2317 |
DOI: | 10.1016/j.redox.2020.101651 |