10.6084/M9.FIGSHARE.C.6309548.V1
Caio Andreeta Figueiredo
Caio Andreeta
Figueiredo
Otto-von-Guericke University Magdeburg
Henning Peter Düsedau
Henning Peter
Düsedau
Otto-von-Guericke University Magdeburg
Johannes Steffen
Johannes
Steffen
Otto-von-Guericke University Magdeburg
Stefanie Ehrentraut
Stefanie
Ehrentraut
Otto-von-Guericke University Magdeburg
Miklos P. Dunay
Miklos P.
Dunay
University of Veterinary Medicine
Gabor Toth
Gabor
Toth
University of Szeged
Dora Reglödi
Dora
Reglödi
University of Pecs
Markus M. Heimesaat
Markus M.
Heimesaat
Charité - University Medicine Berlin
Ildiko Rita Dunay
Ildiko Rita
Dunay
Leibniz Institute for Neurobiology
Otto-von-Guericke University Magdeburg
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 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.
Immunology
figshare
2022
2022-11-21
2022-11-21
Collection
10.1186/s12974-022-02639-z
10.6084/m9.figshare.c.6309548
CC BY 4.0