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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Animals
  • Calcium Signaling / genetics
  • Calcium Signaling / immunology*
  • Calpain / genetics
  • Calpain / immunology*
  • Caspases / genetics
  • Caspases / immunology*
  • Humans
  • Interleukin-16 / genetics
  • Interleukin-16 / immunology*
  • Interleukin-16 / metabolism
  • Methicillin-Resistant Staphylococcus aureus / immunology*
  • Mice
  • Mice, Knockout
  • Pneumonia, Staphylococcal / genetics
  • Pneumonia, Staphylococcal / immunology*
  • Pneumonia, Staphylococcal / metabolism
  • Pneumonia, Staphylococcal / pathology
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / immunology*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Respiratory Mucosa / immunology*
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology

Substances

  • Interleukin-16
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Calpain
  • Caspases