The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment.

Autor: Figueiredo CA; Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany., Düsedau HP; Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany., Steffen J; Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany., Ehrentraut S; Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany., Dunay MP; Department and Clinic of Surgery and Ophthalmology, University of Veterinary Medicine, Budapest, Hungary., Toth G; Department of Medical Chemistry, University of Szeged, Budapest, Hungary., Reglödi D; Department of Anatomy, MTA-PTE PACAP Research Team and Szentagothai Research Center, University of Pecs Medical School, Pecs, Hungary., Heimesaat MM; Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Berlin, Germany., Dunay IR; Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany. ildikodunay@gmail.com.; Center for Behavioral Brain Sciences - CBBS, Magdeburg, Germany. ildikodunay@gmail.com.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2022 Nov 19; Vol. 19 (1), pp. 274. Date of Electronic Publication: 2022 Nov 19.
DOI: 10.1186/s12974-022-02639-z
Abstrakt: 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 p75 NTR , 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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