title: Secretion of IL-16 through TNFR1 and calpain-caspase signaling contributes to MRSA pneumonia.
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.
authors.affiliation: Departments of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Ahn
authors.affiliation: Departments of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: D
authors.initials: D
authors.lastname: Parker
authors.affiliation: Departments of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Planet
authors.affiliation: 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.
authors.forename: P A
authors.initials: PA
authors.lastname: Nieto
authors.affiliation: 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.
authors.forename: S M
authors.initials: SM
authors.lastname: Bueno
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Prince
mesh_terms: D000208:Acute Disease; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology*; D002154:Calpain / Q000235:genetics / Q000276:immunology*; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D006801:Humans; D019410:Interleukin-16 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011023:Pneumonia, Staphylococcal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D019410:Interleukin-16; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D002154:Calpain; D020169:Caspases
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