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Lipoteichoic acid from Staphylococcus aureus increases matrix metalloproteinase 9 expression in RAW 264.7
Luiz Fernando de Souza1, Fernanda Rafaela Jardim, Ismael Pretto Sauter
1Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. lzfsouza@yahoo.com.br
Abstract:
Peptidoglycan (PEG) and lipoteichoic acid (LTA) are the main constituents of Gram-positive bacteria cell wall and are described to modulate immune functions. Increased levels of matrix metalloproteinases (MMPs) were described in endotoxemia, suggesting that they participate to tecidual damage, multiple organs failure and vascular disfunction. Staphylococcus aureus PEG is described to increase MMPs 2 and 9 levels in plasma from rat and MMP 9 secretion by human neutrophils, however, the effect of LTA on MMPs is unknown. In this work, was evaluated the modulation of MMPs 2 and 9 expression and secretion in RAW 264.7 macrophages by LTA from S. aureus. The role of A2A and A2B adenosine receptors was also investigated. LTA increased MMP 9 expression and secretion at 12h of treatment. The modulation of MMP 9 secretion was dose dependent, with maximal effect above 1microg/ml. The inhibitor of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway (U0126, 10microM) prevented LTA stimulation of MMP 9 secretion; however, the inhibitors of p38 (SB203580, 10microM) and Jun N-terminal kinase (JNK; SP600125, 10microM) presented any effect. A2A and A2B adenosine receptors pharmacological blockade or gene knockdown resulted in exacerbated MMP 9 secretion, while an adenosine receptors agonist inhibited LTA-stimulated MMP 9 secretion. These results suggest that LTA increased MMP 9 secretion in macrophages could be involved in complications associated to S. aureus infections. Moreover, LTA modulation of MMP 9 is dependent on MEK/ERK pathway and is regulated by A2A and A2B adenosine receptors.
Insights
Lipoteichoic acid (LTA) from Staphylococcus aureus increases matrix metalloproteinase-9 (MMP-9) secretion in macrophages via the MEK/ERK pathway. Adenosine receptors regulate this process, suggesting a role for LTA in S. aureus infection complications.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- Gram-positive bacteria cell walls contain peptidoglycan (PEG) and lipoteichoic acid (LTA), known immune modulators.
- Elevated matrix metalloproteinases (MMPs) are linked to tissue damage and organ dysfunction in endotoxemia.
- Staphylococcus aureus PEG elevates MMPs 2 and 9, but LTA's effect on MMPs remains unclear.
Purpose of the Study:
- To investigate the effect of S. aureus LTA on MMP-2 and MMP-9 expression and secretion in RAW 264.7 macrophages.
- To explore the involvement of A2A and A2B adenosine receptors in LTA-induced MMP modulation.
Main Methods:
- RAW 264.7 macrophages were treated with S. aureus LTA.
- MMP-9 expression and secretion were measured.
- Specific inhibitors (U0126, SB203580, SP600125) and agonists/antagonists of adenosine receptors were used.
- Gene knockdown of adenosine receptors was performed.
Main Results:
- LTA significantly increased MMP-9 expression and secretion in a dose-dependent manner.
- The MEK/ERK pathway, but not p38 or JNK, was involved in LTA-induced MMP-9 secretion.
- Adenosine receptor blockade or knockdown exacerbated MMP-9 secretion, while an agonist inhibited it.
Conclusions:
- S. aureus LTA stimulates MMP-9 secretion in macrophages, potentially contributing to infection-related complications.
- This modulation is dependent on the MEK/ERK signaling pathway.
- A2A and A2B adenosine receptors play a regulatory role in LTA-induced MMP-9 secretion.
