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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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S. aureus induces IL-16 production in vivo and in vitro(a) C57BL/6J WT mice inoculated with 107 cfu of methicillin resistant S. aureus USA300 (MRSA), S. aureus 502A, K. pneumoniae ST 258 (Kp) or P. aeruginosa strain (PAK) or PBS. Bronchoalveolar lavage fluid(BALF) was obtained 24 hours after infection and quantitated by ELISA. Each dot represents an individual mouse; lines represent median values; data was compiled from 2 independent experiments. *p<0.05 as compared to MRSA, Student's t test, post hoc Dunnett's test. Lines represent median values. (b) THP-1s were stimulated with MRSA, S. aureus 502A, Kp or PAK (MOI 100) *p<0.05 compared to media, Student's t-test, post-hoc Dunnett's test. Graph shown is representative of 2 independent experiments.
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Figure 1: S. aureus induces IL-16 production in vivo and in vitro(a) C57BL/6J WT mice inoculated with 107 cfu of methicillin resistant S. aureus USA300 (MRSA), S. aureus 502A, K. pneumoniae ST 258 (Kp) or P. aeruginosa strain (PAK) or PBS. Bronchoalveolar lavage fluid(BALF) was obtained 24 hours after infection and quantitated by ELISA. Each dot represents an individual mouse; lines represent median values; data was compiled from 2 independent experiments. *p<0.05 as compared to MRSA, Student's t test, post hoc Dunnett's test. Lines represent median values. (b) THP-1s were stimulated with MRSA, S. aureus 502A, Kp or PAK (MOI 100) *p<0.05 compared to media, Student's t-test, post-hoc Dunnett's test. Graph shown is representative of 2 independent experiments.

Mentions: Significantly higher levels of IL-16 were recovered from the bronchoalveolar lavage fluid (BALF) of WT mice infected with 107 cfu methicillin resistant S. aureus USA300 (MRSA) strain (p=0.0001 compared to PBS) or S. aureus 502A, a representative methicillin sensitive strain. Lower levels were retrieved from mice infected with 107 cfu of Gram negative organisms such as Klebsiella pneumoniae ST 258 and Pseudomonas aeruginosa PAK (p<0.05 compared to MRSA) (Figure 1a). To determine if human cells similarly had differential IL-16 responses to S. aureus versus Gram negative stimuli the human monocytic cells, THP-1s were stimulated with the same pathogens. IL-16 from THP-1s was 18-fold higher than the media control after incubation with MRSA (p=0.0001) and 20-fold after infection with S. aureus 502A. Less IL-16 was measured in response to infection with Kp or PAK (p<0.05 compared to MRSA) (Figure 1b).


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)

S. aureus induces IL-16 production in vivo and in vitro(a) C57BL/6J WT mice inoculated with 107 cfu of methicillin resistant S. aureus USA300 (MRSA), S. aureus 502A, K. pneumoniae ST 258 (Kp) or P. aeruginosa strain (PAK) or PBS. Bronchoalveolar lavage fluid(BALF) was obtained 24 hours after infection and quantitated by ELISA. Each dot represents an individual mouse; lines represent median values; data was compiled from 2 independent experiments. *p<0.05 as compared to MRSA, Student's t test, post hoc Dunnett's test. Lines represent median values. (b) THP-1s were stimulated with MRSA, S. aureus 502A, Kp or PAK (MOI 100) *p<0.05 compared to media, Student's t-test, post-hoc Dunnett's test. Graph shown is representative of 2 independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4199935&req=5

Figure 1: S. aureus induces IL-16 production in vivo and in vitro(a) C57BL/6J WT mice inoculated with 107 cfu of methicillin resistant S. aureus USA300 (MRSA), S. aureus 502A, K. pneumoniae ST 258 (Kp) or P. aeruginosa strain (PAK) or PBS. Bronchoalveolar lavage fluid(BALF) was obtained 24 hours after infection and quantitated by ELISA. Each dot represents an individual mouse; lines represent median values; data was compiled from 2 independent experiments. *p<0.05 as compared to MRSA, Student's t test, post hoc Dunnett's test. Lines represent median values. (b) THP-1s were stimulated with MRSA, S. aureus 502A, Kp or PAK (MOI 100) *p<0.05 compared to media, Student's t-test, post-hoc Dunnett's test. Graph shown is representative of 2 independent experiments.
Mentions: Significantly higher levels of IL-16 were recovered from the bronchoalveolar lavage fluid (BALF) of WT mice infected with 107 cfu methicillin resistant S. aureus USA300 (MRSA) strain (p=0.0001 compared to PBS) or S. aureus 502A, a representative methicillin sensitive strain. Lower levels were retrieved from mice infected with 107 cfu of Gram negative organisms such as Klebsiella pneumoniae ST 258 and Pseudomonas aeruginosa PAK (p<0.05 compared to MRSA) (Figure 1a). To determine if human cells similarly had differential IL-16 responses to S. aureus versus Gram negative stimuli the human monocytic cells, THP-1s were stimulated with the same pathogens. IL-16 from THP-1s was 18-fold higher than the media control after incubation with MRSA (p=0.0001) and 20-fold after infection with S. aureus 502A. Less IL-16 was measured in response to infection with Kp or PAK (p<0.05 compared to MRSA) (Figure 1b).

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