Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis
Abstract Background Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1...
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| Format: | Article |
| Language: | English |
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BMC
2017-11-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-017-0989-0 |
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| author | Ilias Masouris Matthias Klein Susanne Dyckhoff Barbara Angele H. W. Pfister Uwe Koedel |
| author_facet | Ilias Masouris Matthias Klein Susanne Dyckhoff Barbara Angele H. W. Pfister Uwe Koedel |
| author_sort | Ilias Masouris |
| collection | DOAJ |
| description | Abstract Background Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1), plays a major role in persistence of inflammation. In this study, we evaluated if paquinimod, an MRP14-inhibitor, and an anti-HMGB1 antibody can improve clinical outcome as adjunctive therapeutics in pneumococcal meningitis. Methods We tested the adjuvant administration of paquinimod and the anti-HMGB1 antibody in our pneumococcal meningitis mouse model assessing clinical (clinical score, open-field-test, temperature) and pathophysiological parameters (intracranial pressure, white blood cell count in CSF, bleeding area) as well as bacterial titers in blood and brain 24 h after administration and 48 h after infection. Furthermore, we explored the interactions of these two agents with dexamethasone, the standard adjuvant treatment in pneumococcal meningitis (PM), and daptomycin, a non-bacteriolytic antibiotic preventing pathogen-associated molecular pattern (PAMP) release. Results Adjunctive inhibition of MRP14 or HMGB1 reduced mortality in mice with PM. This effect was lost when the two anti-DAMP agents were given simultaneously, possibly due to excessive immunosuppression. Combining anti-PAMP (daptomycin) and anti-DAMP treatments did not produce synergistic results; instead, the anti-DAMP treatment alone was sufficient and superior. The combination of anti-HMGB1 with dexamethasone did not diminish the effect of the former. Conclusions DAMP inhibition possesses good potential as an adjuvant treatment approach in PM, as it improves clinical outcome and can be given together with the standard adjuvant dexamethasone without drug effect loss in experimental PM. |
| first_indexed | 2024-12-21T09:51:01Z |
| format | Article |
| id | doaj.art-b75107f185e447fca484185ff254218a |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-21T09:51:01Z |
| publishDate | 2017-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-b75107f185e447fca484185ff254218a2022-12-21T19:08:11ZengBMCJournal of Neuroinflammation1742-20942017-11-011411910.1186/s12974-017-0989-0Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitisIlias Masouris0Matthias Klein1Susanne Dyckhoff2Barbara Angele3H. W. Pfister4Uwe Koedel5Department of Neurology, University Hospital, LMU MunichDepartment of Neurology, University Hospital, LMU MunichDepartment of Neurology, University Hospital, LMU MunichDepartment of Neurology, University Hospital, LMU MunichDepartment of Neurology, University Hospital, LMU MunichDepartment of Neurology, University Hospital, LMU MunichAbstract Background Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1), plays a major role in persistence of inflammation. In this study, we evaluated if paquinimod, an MRP14-inhibitor, and an anti-HMGB1 antibody can improve clinical outcome as adjunctive therapeutics in pneumococcal meningitis. Methods We tested the adjuvant administration of paquinimod and the anti-HMGB1 antibody in our pneumococcal meningitis mouse model assessing clinical (clinical score, open-field-test, temperature) and pathophysiological parameters (intracranial pressure, white blood cell count in CSF, bleeding area) as well as bacterial titers in blood and brain 24 h after administration and 48 h after infection. Furthermore, we explored the interactions of these two agents with dexamethasone, the standard adjuvant treatment in pneumococcal meningitis (PM), and daptomycin, a non-bacteriolytic antibiotic preventing pathogen-associated molecular pattern (PAMP) release. Results Adjunctive inhibition of MRP14 or HMGB1 reduced mortality in mice with PM. This effect was lost when the two anti-DAMP agents were given simultaneously, possibly due to excessive immunosuppression. Combining anti-PAMP (daptomycin) and anti-DAMP treatments did not produce synergistic results; instead, the anti-DAMP treatment alone was sufficient and superior. The combination of anti-HMGB1 with dexamethasone did not diminish the effect of the former. Conclusions DAMP inhibition possesses good potential as an adjuvant treatment approach in PM, as it improves clinical outcome and can be given together with the standard adjuvant dexamethasone without drug effect loss in experimental PM.http://link.springer.com/article/10.1186/s12974-017-0989-0Streptococcus pneumoniaeMeningitisHMGB1PaquinimodAdjuvant treatment |
| spellingShingle | Ilias Masouris Matthias Klein Susanne Dyckhoff Barbara Angele H. W. Pfister Uwe Koedel Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis Journal of Neuroinflammation Streptococcus pneumoniae Meningitis HMGB1 Paquinimod Adjuvant treatment |
| title | Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis |
| title_full | Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis |
| title_fullStr | Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis |
| title_full_unstemmed | Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis |
| title_short | Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis |
| title_sort | inhibition of damp signaling as an effective adjunctive treatment strategy in pneumococcal meningitis |
| topic | Streptococcus pneumoniae Meningitis HMGB1 Paquinimod Adjuvant treatment |
| url | http://link.springer.com/article/10.1186/s12974-017-0989-0 |
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