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

Ahn DS, Parker D, Planet PJ, Nieto PA, Bueno SM, Prince A - Mucosal Immunol (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pediatrics, Columbia University College of Physicians and Surgeons, 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.

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TNFR1 is involved in IL-16 secretionAge and sex matched cohorts of C57BL/6J WT and Tnfr1−/− mice were inoculated with 107 cfu of MRSA or PBS for 24 hours. BALF was quantitated for (a) IL-16 by ELISA, (b) total protein (c) and KC by ELISA. (d) H&E sections of fixed whole lungs. Magnification 100x. (e) Bacterial cfus were counted in BALF. (f) Neutrophils (PMNs) (Ly6G+/MHCII− ) and (g) Macrophages (CD11c+/MHCIIlow-mid) in the BALF, as well as CD4+ cells in lung homogenate (h) were enumerated by flow cytometry. Each dot represents an individual mouse and is compiled from 3 independent experiments. Lines represent median values.
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Figure 3: TNFR1 is involved in IL-16 secretionAge and sex matched cohorts of C57BL/6J WT and Tnfr1−/− mice were inoculated with 107 cfu of MRSA or PBS for 24 hours. BALF was quantitated for (a) IL-16 by ELISA, (b) total protein (c) and KC by ELISA. (d) H&E sections of fixed whole lungs. Magnification 100x. (e) Bacterial cfus were counted in BALF. (f) Neutrophils (PMNs) (Ly6G+/MHCII− ) and (g) Macrophages (CD11c+/MHCIIlow-mid) in the BALF, as well as CD4+ cells in lung homogenate (h) were enumerated by flow cytometry. Each dot represents an individual mouse and is compiled from 3 independent experiments. Lines represent median values.

Mentions: TNFR1 ligation activates caspase-3 signaling23, important in the processing of pro-IL-16 to its active form22 and is stimulated by the IgG binding domain of SpA10. To establish the importance of TNFR1 mediated signaling in the induction of IL-16 production, we compared generation of IL-16 in WT and Tnfr1−/− mice (Figure 3). There was significantly less IL-16 in the BALF of infected Tnfr1−/− mice compared to WT controls (p<0.05) (Figure 3a). Protein content in the BALF was slightly lower in the KO mice (Figure 3b) with similar levels of KC (Figure 3c). Histopathology of Tnfr1−/− lungs infected with MRSA suggested less destruction of the normal architecture than WT mouse lung (Figure 3d), consistent with previous reports10. Numbers of bacteria recovered in BALF were similar (Figure 3e) and recruited innate immune cells into BALF and lung were not significantly different in the WT and Tnfr1−/− mice (Figure 3f-h). Participation of TNFR1 in IL-16 processing is evident, but incomplete attenuation of IL-16 production in Tnfr1−/− mice suggests that other pathways are involved.


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

Ahn DS, Parker D, Planet PJ, Nieto PA, Bueno SM, Prince A - Mucosal Immunol (2014)

TNFR1 is involved in IL-16 secretionAge and sex matched cohorts of C57BL/6J WT and Tnfr1−/− mice were inoculated with 107 cfu of MRSA or PBS for 24 hours. BALF was quantitated for (a) IL-16 by ELISA, (b) total protein (c) and KC by ELISA. (d) H&E sections of fixed whole lungs. Magnification 100x. (e) Bacterial cfus were counted in BALF. (f) Neutrophils (PMNs) (Ly6G+/MHCII− ) and (g) Macrophages (CD11c+/MHCIIlow-mid) in the BALF, as well as CD4+ cells in lung homogenate (h) were enumerated by flow cytometry. Each dot represents an individual mouse and is compiled from 3 independent experiments. Lines represent median values.
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Related In: Results  -  Collection

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Figure 3: TNFR1 is involved in IL-16 secretionAge and sex matched cohorts of C57BL/6J WT and Tnfr1−/− mice were inoculated with 107 cfu of MRSA or PBS for 24 hours. BALF was quantitated for (a) IL-16 by ELISA, (b) total protein (c) and KC by ELISA. (d) H&E sections of fixed whole lungs. Magnification 100x. (e) Bacterial cfus were counted in BALF. (f) Neutrophils (PMNs) (Ly6G+/MHCII− ) and (g) Macrophages (CD11c+/MHCIIlow-mid) in the BALF, as well as CD4+ cells in lung homogenate (h) were enumerated by flow cytometry. Each dot represents an individual mouse and is compiled from 3 independent experiments. Lines represent median values.
Mentions: TNFR1 ligation activates caspase-3 signaling23, important in the processing of pro-IL-16 to its active form22 and is stimulated by the IgG binding domain of SpA10. To establish the importance of TNFR1 mediated signaling in the induction of IL-16 production, we compared generation of IL-16 in WT and Tnfr1−/− mice (Figure 3). There was significantly less IL-16 in the BALF of infected Tnfr1−/− mice compared to WT controls (p<0.05) (Figure 3a). Protein content in the BALF was slightly lower in the KO mice (Figure 3b) with similar levels of KC (Figure 3c). Histopathology of Tnfr1−/− lungs infected with MRSA suggested less destruction of the normal architecture than WT mouse lung (Figure 3d), consistent with previous reports10. Numbers of bacteria recovered in BALF were similar (Figure 3e) and recruited innate immune cells into BALF and lung were not significantly different in the WT and Tnfr1−/− mice (Figure 3f-h). Participation of TNFR1 in IL-16 processing is evident, but incomplete attenuation of IL-16 production in Tnfr1−/− mice suggests that other pathways are involved.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pediatrics, Columbia University College of Physicians and Surgeons, 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.

Show MeSH
Related in: MedlinePlus