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A beta-lactam antibiotic dampens excitotoxic inflammatory CNS damage in a mouse model of multiple sclerosis
Nico Melzer1, Sven G Meuth, Delany Torres-Salazar
1Department of Neurology, University of Würzburg, Würzburg, Germany.
Abstract:
In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), impairment of glial "Excitatory Amino Acid Transporters" (EAATs) together with an excess glutamate-release by invading immune cells causes excitotoxic damage of the central nervous system (CNS). In order to identify pathways to dampen excitotoxic inflammatory CNS damage, we assessed the effects of a beta-lactam antibiotic, ceftriaxone, reported to enhance expression of glial EAAT2, in "Myelin Oligodendrocyte Glycoprotein" (MOG)-induced EAE. Ceftriaxone profoundly ameliorated the clinical course of murine MOG-induced EAE both under preventive and therapeutic regimens. However, ceftriaxone had impact neither on EAAT2 protein expression levels in several brain areas, nor on the radioactive glutamate uptake capacity in a mixed primary glial cell-culture and the glutamate-induced uptake currents in a mammalian cell line mediated by EAAT2. Moreover, the clinical effect of ceftriaxone was preserved in the presence of the EAAT2-specific transport inhibitor, dihydrokainate, while dihydrokainate alone caused an aggravated EAE course. This demonstrates the need for sufficient glial glutamate uptake upon an excitotoxic autoimmune inflammatory challenge of the CNS and a molecular target of ceftriaxone other than the glutamate transporter. Ceftriaxone treatment indirectly hampered T cell proliferation and proinflammatory INFgamma and IL17 secretion through modulation of myelin-antigen presentation by antigen-presenting cells (APCs) e.g. dendritic cells (DCs) and reduced T cell migration into the CNS in vivo. Taken together, we demonstrate, that a beta-lactam antibiotic attenuates disease course and severity in a model of autoimmune CNS inflammation. The mechanisms are reduction of T cell activation by modulation of cellular antigen-presentation and impairment of antigen-specific T cell migration into the CNS rather than or modulation of central glutamate homeostasis.
Insights
The beta-lactam antibiotic ceftriaxone significantly reduced symptoms in a mouse model of multiple sclerosis (MS). This effect was not due to altered glutamate transport but by dampening immune cell activation and migration into the central nervous system (CNS).
Area of Science:
- Neuroimmunology
- Pharmacology
- Neuroinflammation
Background:
- Glutamate excitotoxicity, mediated by impaired Excitatory Amino Acid Transporters (EAATs), contributes to central nervous system (CNS) damage in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).
- Ceftriaxone, a beta-lactam antibiotic, was investigated for its potential to enhance glial EAAT2 expression and mitigate EAE.
Purpose of the Study:
- To investigate the therapeutic potential of ceftriaxone in a murine model of MS (MOG-induced EAE).
- To elucidate the underlying mechanisms of ceftriaxone's action, particularly its effect on glial glutamate transporters and immune cell responses.
Main Methods:
- Murine experimental autoimmune encephalomyelitis (EAE) was induced using myelin oligodendrocyte glycoprotein (MOG).
- Ceftriaxone was administered preventively and therapeutically.
- EAAT2 protein levels, glutamate uptake capacity, and glutamate-induced currents were assessed.
- The impact of ceftriaxone and the EAAT2 inhibitor dihydrokainate on EAE severity was evaluated.
- T cell proliferation, cytokine secretion (INFgamma, IL17), antigen presentation by dendritic cells (DCs), and T cell migration into the CNS were analyzed.
Main Results:
- Ceftriaxone significantly ameliorated the clinical course of MOG-induced EAE.
- No significant changes in EAAT2 protein levels or glutamate uptake function were observed.
- Ceftriaxone's therapeutic effect persisted despite inhibition of EAAT2.
- Dihydrokainate alone exacerbated EAE, highlighting the importance of glial glutamate uptake.
- Ceftriaxone reduced T cell proliferation, INFgamma and IL17 secretion, modulated antigen presentation by APCs/DCs, and decreased T cell infiltration into the CNS.
Conclusions:
- Ceftriaxone attenuates autoimmune CNS inflammation in a mouse model of MS.
- The therapeutic benefits of ceftriaxone are mediated by modulating T cell activation and migration, rather than altering central glutamate homeostasis via EAAT2.
- These findings suggest ceftriaxone as a potential therapeutic agent for MS by targeting immune cell responses.
