The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment
Abstract Background Cerebral infection with the protozoan Toxoplasma gondii (T. gondii) is responsible for inflammation of the central nervous system (CNS) contributing to subtle neuronal alterations. Albeit essential for brain parasite control, continuous microglia activation and recruitment of per...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02639-z |
| _version_ | 1828094248231108608 |
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| author | Caio Andreeta Figueiredo Henning Peter Düsedau Johannes Steffen Stefanie Ehrentraut Miklos P. Dunay Gabor Toth Dora Reglödi Markus M. Heimesaat Ildiko Rita Dunay |
| author_facet | Caio Andreeta Figueiredo Henning Peter Düsedau Johannes Steffen Stefanie Ehrentraut Miklos P. Dunay Gabor Toth Dora Reglödi Markus M. Heimesaat Ildiko Rita Dunay |
| author_sort | Caio Andreeta Figueiredo |
| collection | DOAJ |
| description | Abstract Background Cerebral infection with the protozoan Toxoplasma gondii (T. gondii) is responsible for inflammation of the central nervous system (CNS) contributing to subtle neuronal alterations. Albeit essential for brain parasite control, continuous microglia activation and recruitment of peripheral immune cells entail distinct neuronal impairment upon infection-induced neuroinflammation. PACAP is an endogenous neuropeptide known to inhibit inflammation and promote neuronal survival. Since PACAP is actively transported into the CNS, we aimed to assess the impact of PACAP on the T. gondii-induced neuroinflammation and subsequent effects on neuronal homeostasis. Methods Exogenous PACAP was administered intraperitoneally in the chronic stage of T. gondii infection, and brains were isolated for histopathological analysis and determination of pathogen levels. Immune cells from the brain, blood, and spleen were analyzed by flow cytometry, and the further production of inflammatory mediators was investigated by intracellular protein staining as well as expression levels by RT-qPCR. Neuronal and synaptic alterations were assessed on the transcriptional and protein level, focusing on neurotrophins, neurotrophin-receptors and signature synaptic markers. Results Here, we reveal that PACAP administration reduced the inflammatory foci and the number of apoptotic cells in the brain parenchyma and restrained the activation of microglia and recruitment of monocytes. The neuropeptide reduced the expression of inflammatory mediators such as IFN-γ, IL-6, iNOS, and IL-1β. Moreover, PACAP diminished IFN-γ production by recruited CD4+ T cells in the CNS. Importantly, PACAP promoted neuronal health via increased expression of the neurotrophin BDNF and reduction of p75NTR, a receptor related to neuronal cell death. In addition, PACAP administration was associated with increased expression of transporters involved in glutamatergic and GABAergic signaling that are particularly affected during cerebral toxoplasmosis. Conclusions Together, our findings unravel the beneficial effects of exogenous PACAP treatment upon infection-induced neuroinflammation, highlighting the potential implication of neuropeptides to promote neuronal survival and minimize synaptic prejudice. |
| first_indexed | 2024-04-11T06:57:15Z |
| format | Article |
| id | doaj.art-de87aabd1e0c487c8a7594650d117f9a |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T06:57:15Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-de87aabd1e0c487c8a7594650d117f9a2022-12-22T04:39:01ZengBMCJournal of Neuroinflammation1742-20942022-11-0119111710.1186/s12974-022-02639-zThe neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairmentCaio Andreeta Figueiredo0Henning Peter Düsedau1Johannes Steffen2Stefanie Ehrentraut3Miklos P. Dunay4Gabor Toth5Dora Reglödi6Markus M. Heimesaat7Ildiko Rita Dunay8Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke UniversityInstitute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke UniversityInstitute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke UniversityInstitute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke UniversityDepartment and Clinic of Surgery and Ophthalmology, University of Veterinary MedicineDepartment of Medical Chemistry, University of SzegedDepartment of Anatomy, MTA-PTE PACAP Research Team and Szentagothai Research Center, University of Pecs Medical SchoolInstitute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine BerlinInstitute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke UniversityAbstract Background Cerebral infection with the protozoan Toxoplasma gondii (T. gondii) is responsible for inflammation of the central nervous system (CNS) contributing to subtle neuronal alterations. Albeit essential for brain parasite control, continuous microglia activation and recruitment of peripheral immune cells entail distinct neuronal impairment upon infection-induced neuroinflammation. PACAP is an endogenous neuropeptide known to inhibit inflammation and promote neuronal survival. Since PACAP is actively transported into the CNS, we aimed to assess the impact of PACAP on the T. gondii-induced neuroinflammation and subsequent effects on neuronal homeostasis. Methods Exogenous PACAP was administered intraperitoneally in the chronic stage of T. gondii infection, and brains were isolated for histopathological analysis and determination of pathogen levels. Immune cells from the brain, blood, and spleen were analyzed by flow cytometry, and the further production of inflammatory mediators was investigated by intracellular protein staining as well as expression levels by RT-qPCR. Neuronal and synaptic alterations were assessed on the transcriptional and protein level, focusing on neurotrophins, neurotrophin-receptors and signature synaptic markers. Results Here, we reveal that PACAP administration reduced the inflammatory foci and the number of apoptotic cells in the brain parenchyma and restrained the activation of microglia and recruitment of monocytes. The neuropeptide reduced the expression of inflammatory mediators such as IFN-γ, IL-6, iNOS, and IL-1β. Moreover, PACAP diminished IFN-γ production by recruited CD4+ T cells in the CNS. Importantly, PACAP promoted neuronal health via increased expression of the neurotrophin BDNF and reduction of p75NTR, a receptor related to neuronal cell death. In addition, PACAP administration was associated with increased expression of transporters involved in glutamatergic and GABAergic signaling that are particularly affected during cerebral toxoplasmosis. Conclusions Together, our findings unravel the beneficial effects of exogenous PACAP treatment upon infection-induced neuroinflammation, highlighting the potential implication of neuropeptides to promote neuronal survival and minimize synaptic prejudice.https://doi.org/10.1186/s12974-022-02639-zPACAPNeuroinflammationToxoplasma gondiiCerebral toxoplasmosisImmunomodulationNeuroprotection |
| spellingShingle | Caio Andreeta Figueiredo Henning Peter Düsedau Johannes Steffen Stefanie Ehrentraut Miklos P. Dunay Gabor Toth Dora Reglödi Markus M. Heimesaat Ildiko Rita Dunay The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment Journal of Neuroinflammation PACAP Neuroinflammation Toxoplasma gondii Cerebral toxoplasmosis Immunomodulation Neuroprotection |
| title | The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment |
| title_full | The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment |
| title_fullStr | The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment |
| title_full_unstemmed | The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment |
| title_short | The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment |
| title_sort | neuropeptide pacap alleviates t gondii infection induced neuroinflammation and neuronal impairment |
| topic | PACAP Neuroinflammation Toxoplasma gondii Cerebral toxoplasmosis Immunomodulation Neuroprotection |
| url | https://doi.org/10.1186/s12974-022-02639-z |
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