A LTB4/CD11b self-amplifying loop drives pyogranuloma formation in chronic granulomatous disease
Kelsey C. Haist,
Sophie L. Gibbings,
Jordan Jacobelli,
Kara J. Mould,
Peter M. Henson,
Donna L. Bratton
Affiliations
Kelsey C. Haist
National Jewish Health, Department of Pediatrics, Denver, CO 80206, USA; Corresponding author
Sophie L. Gibbings
National Jewish Health, Department of Pediatrics, Denver, CO 80206, USA
Jordan Jacobelli
University of Colorado, Anschutz Medical Campus, Department of Immunology and Microbiology, Barbara Davis Research Center, Aurora, CO 80045, USA
Kara J. Mould
National Jewish Health, Department of Medicine, Denver, CO 80206, USA; University of Colorado, Anschutz Medical Campus, Department of Pulmonary and Critical Care Medicine, Aurora, CO 80045, USA
Peter M. Henson
National Jewish Health, Department of Pediatrics, Denver, CO 80206, USA; University of Colorado, Anschutz Medical Campus, Department of Immunology and Microbiology, Barbara Davis Research Center, Aurora, CO 80045, USA; National Jewish Health, Department of Medicine, Denver, CO 80206, USA; University of Colorado, Anschutz Medical Campus, Department of Pulmonary and Critical Care Medicine, Aurora, CO 80045, USA
Donna L. Bratton
National Jewish Health, Department of Pediatrics, Denver, CO 80206, USA; University of Colorado, Anschutz Medical Campus, Department of Pediatrics, Aurora, CO 80045, USA
Summary: Sterile pyogranulomas and heightened cytokine production are hyperinflammatory hallmarks of Chronic Granulomatous Disease (CGD). Using peritoneal cells of zymosan-treated CGD (gp91phox−/−) 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. LTB4 was key, as antagonizing BLT1 blocked neutrophil aggregation, but acted only indirectly on MoMac recruitment. LTB4 upregulated CD11b expression on CGD neutrophils, and the absence/blockade of CD11b inhibited LTB4 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.
