A LTB4/CD11b self-amplifying loop drives pyogranuloma formation in chronic granulomatous disease
Year: 2024
Type: article
Abstract: Sterile pyogranulomas and heightened cytokine production are hyperinflammatory hallmarks of Chronic Granulomatous Disease (CGD). Using peritoneal cells of zymosan-treated CGD (gp91 phox−/− ) versus wild-type (WT) mice, an ex vivo system of pyogranuloma formation was developed to determine factors involved in and consequences of recruitment of neutrophils and monocyte-derived macrophages (MoMacs). Whereas WT cells failed to aggregate, CGD cells formed aggregates containing neutrophils initially, and MoMacs recruited secondarily. LTB 4 was key, as antagonizing BLT1 blocked neutrophil aggregation, but acted only indirectly on MoMac recruitment. LTB 4 upregulated CD11b expression on CGD neutrophils, and the absence/blockade of CD11b inhibited LTB 4 production and cell aggregation. Neutrophil-dependent MoMac recruitment was independent of MoMac Nox2 status, BLT1, CCR1, CCR2, CCR5, CXCR2, and CXCR6. As proof of concept, CD11b-deficient CGD mice developed disrupted pyogranulomas with poorly organized neutrophils and diminished recruitment of MoMacs. Importantly, the disruption of cell aggregation and pyogranuloma formation markedly reduced proinflammatory cytokine production.
Source: iScience
Institutions: National Jewish Health, University of Colorado Anschutz
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,150
Awards: Neutrophil Nox2 controls mononuclear cell functions in inflammation; role in CGD, G2708028384, Metabolic Reprogramming of Recruited Alveolar Macrophages by Arginine In Acute Lung Injury, G7947400208, Roles for interstitial and airspace macrophages in resolution of pulmonary inflammation, G8887800790
OpenAlex ID: W4393226594