NADPH Oxidase Limits Collaborative Pattern-Recognition Receptor Signaling to Regulate Neutrophil Cytokine Production in Response to Fungal Pathogen-Associated Molecular Patterns.
J Immunol
; 207(3): 923-937, 2021 08 01.
Article
em En
| MEDLINE
| ID: mdl-34301842
ABSTRACT
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by genetic defects in leukocyte NADPH oxidase, which has both microbicidal and immunomodulatory roles. Hence, CGD is characterized by recurrent bacterial and fungal infections as well as aberrant inflammation. Fungal cell walls induce neutrophilic inflammation in CGD; yet, underlying mechanisms are incompletely understood. This study investigated the receptors and signaling pathways driving aberrant proinflammatory cytokine production in CGD neutrophils activated by fungal cell walls. Although cytokine responses to ß-glucan particles were similar in NADPH oxidase-competent and NADPH oxidase-deficient mouse and human neutrophils, stimulation with zymosan, a more complex fungal particle, induced elevated cytokine production in NADPH oxidase-deficient neutrophils. The dectin-1 C-type lectin receptor, which recognizes ß-glucans (1-3), and TLRs mediated cytokine responses by wild-type murine neutrophils. In the absence of NADPH oxidase, fungal pathogen-associated molecular patterns engaged additional collaborative signaling with Mac-1 and TLRs to markedly increase cytokine production. Mechanistically, this cytokine overproduction is mediated by enhanced proximal activation of tyrosine phosphatase SHP2-Syk and downstream Card9-dependent NF-κB and Card9-independent JNK-c-Jun. This activation and amplified cytokine production were significantly decreased by exogenous H2O2 treatment, enzymatic generation of exogenous H2O2, or Mac-1 blockade. Similar to zymosan, Aspergillus fumigatus conidia induced increased signaling in CGD mouse neutrophils for activation of proinflammatory cytokine production, which also used Mac-1 and was Card9 dependent. This study, to our knowledge, provides new insights into how NADPH oxidase deficiency deregulates neutrophil cytokine production in response to fungal cell walls.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aspergillus fumigatus
/
Antígeno de Macrófago 1
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Lectinas Tipo C
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Receptores de Reconhecimento de Padrão
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NADPH Oxidase 2
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Doença Granulomatosa Crônica
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Neutrófilos
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2021
Tipo de documento:
Article