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Mucosal Immunol. 2014 Nov;7(6):1366-74. doi: 10.1038/mi.2014.24. Epub 2014 Apr 16.

Secretion of IL-16 through TNFR1 and calpain-caspase signaling contributes to MRSA pneumonia.

Author information

1
Departments of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA.
2
1] Millennium Institute on Immunology and Immunotherapy, Santiago, Chile [2] Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
3
1] Departments of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA [2] Department of Pharmacology, Columbia University College of Physicians and Surgeon, New York, New York, USA.

Abstract

Staphylococcus aureus is a major cause of severe pneumonia. Multiple mechanisms of proinflammatory signaling are activated to recruit immune cells into the airway in response to S. aureus. We found that interleukin-16 (IL-16), a T cell cytokine that binds CD4, is potently activated by S. aureus, specifically by protein A (SpA), and to a much greater extent than by Gram-negative pathogens or lipopolysaccharide. IL-16 production involved multiple signals including ligation of tumor necrosis factor receptor (TNFR) family members or epidermal growth factor receptor, both receptors for SpA and generation of Ca(2+) fluxes to activate calpains and caspase-3. Although human airway epithelial cells, vascular endothelial cells, THP-1 and Jurkat T cells released IL-16 in response to S. aureus in vitro, in a murine model of pneumonia, CD4(+) cells were the major source of IL-16 suggesting the involvement of an autocrine signaling pathway. The production of IL-16 contributed to lung damage as neutralization of IL-16 enhanced S. aureus clearance and resulted in diminished lung pathology in S. aureus pneumonia. Our results suggest that the ability of S. aureus to activate TNFR1 and Ca(2+)/calpain signaling contribute to T cell activation and excessive inflammation in the setting of acute pneumonia.

PMID:
24736233
PMCID:
PMC4199935
DOI:
10.1038/mi.2014.24
[Indexed for MEDLINE]
Free PMC Article

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