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Published on: August 11, 2023
Dexamethasone along with ciprofloxacin modulates S. aureus induced microglial inflammation via glucocorticoid (GC)-GC
1Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, Calcutta, West Bengal, India.
Abstract:
Microglial inflammation is the hallmark of S. aureus induced brain abscesses. Conventional antibiotic therapy could not regulate inflammation and the use of steroids in CNS infection remained controversial. To address this issue the effect of dexamethasone along with ciprofloxacin on microglial inflammation has been attempted both in glucocorticoid receptor (GR) opened and blocked condition. We have investigated the effects of ciprofloxacin (0.24 μg/ml, pre-treatment) and dexamethasone (150 nM, pre-treatment) in combination with murine microglia infected with S. aureus for 30, 60 and 90 min by either keeping GR opened or blocked with GR antagonist RU486. Alterations in cellular motility, intracellular killing assay, free radical production, antioxidant enzyme activities, corticosterone, and cytokine levels were determined. The expressions of TLR-2, GR, and other inflammatory markers were determined in terms of this combinatorial treatment. Combination treatment significantly (p < 0.05) reduced the bacterial burden of microglia only when GR remained open and effectively suppressed S. aureus induced oxidative stress by augmenting SOD and catalase enzyme activity and suppressing other pro-inflammatory markers at 90 min. Arginase activity, a critical determinant of microglial polarization was found to be higher after treatment at 60 and 90 min. This situation was reversed when this combination treatment was applied by keeping GR blocked using GR antagonist RU486. Therefore, it can be concluded that combination treatment of ciprofloxacin and dexamethasone could regulate S. aureus induced microglial activation, in the presence of functional GR via utilizing glucocorticoid (GC)-GR pathway and ultimately confers protection to the host from brain inflammation.
Insights
Combination therapy with ciprofloxacin and dexamethasone effectively reduced Staphylococcus aureus (S. aureus) induced microglial inflammation and oxidative stress in brain abscesses when the glucocorticoid receptor (GR) was functional. This treatment suppressed inflammatory markers and bacterial burden, conferring host protection.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglial inflammation is central to Staphylococcus aureus (S. aureus) induced brain abscesses.
- Conventional antibiotics are insufficient for inflammation control, and steroid use in CNS infections is debated.
- The role of glucocorticoid receptor (GR) in modulating microglial responses to S. aureus is not fully understood.
Purpose of the Study:
- To investigate the combined effect of dexamethasone and ciprofloxacin on microglial inflammation in S. aureus brain abscesses.
- To determine the influence of glucocorticoid receptor (GR) status (opened vs. blocked) on the efficacy of this combination therapy.
- To assess the impact of the treatment on bacterial burden, oxidative stress, cellular functions, and inflammatory markers.
Main Methods:
- Murine microglia were infected with S. aureus and pre-treated with ciprofloxacin and dexamethasone.
- Experiments were conducted with GR either open or blocked using the GR antagonist RU486.
- Assays included cellular motility, intracellular killing, free radical production, antioxidant enzyme activities, corticosterone, cytokine levels, arginase activity, and expression of TLR-2 and GR.
Main Results:
- The combination treatment significantly reduced bacterial burden and S. aureus-induced oxidative stress only when GR was open.
- The therapy enhanced SOD and catalase activity, suppressed pro-inflammatory markers at 90 min, and increased arginase activity at 60 and 90 min.
- Blocking GR with RU486 reversed these beneficial effects, indicating the critical role of the GC-GR pathway.
Conclusions:
- Combination treatment of ciprofloxacin and dexamethasone effectively regulates S. aureus-induced microglial activation via the GC-GR pathway when GR is functional.
- This combinatorial approach suppresses inflammation and oxidative stress, offering potential protection against brain abscesses.
- The findings highlight the importance of GR signaling in mediating the therapeutic effects of combined antibiotic and steroid treatment in CNS infections.
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