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 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 LPS. IL-16 production involved multiple signals including ligation of TNFR family members or EGFR, both receptors for SpA and generation of Ca2+ 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 Ca2+/calpain signaling contribute to T cell activation and excessive inflammation in the setting of acute pneumonia.