Abstract
Adverse psychosocial experiences have been shown to modulate individual responses to immune challenges and affect mitochondrial functions. The aim of this study was to investigate inflammation and immune responses as well as mitochondrial bioenergetics in an experimental model of Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). Starting in adolescence (postnatal day 28), male SJL/J mice were exposed to five injections (interspaced by two weeks) with Group-A beta-haemolytic streptococcus (GAS) homogenate. Mice were exposed to chronic psychosocial stress, in the form of protracted visual exposure to an aggressive conspecific, for four weeks. Our results indicate that psychosocial stress exacerbated individual response to GAS administrations whereby mice exposed to both treatments exhibited altered cytokine and immune-related enzyme expression in the hippocampus and hypothalamus. Additionally, they showed impaired mitochondrial respiratory chain complexes IV and V, and reduced adenosine triphosphate (ATP) production by mitochondria and ATP content. These brain abnormalities, observed in GAS-Stress mice, were associated with blunted titers of plasma corticosterone. Present data support the hypothesis that challenging environmental conditions, in terms of chronic psychosocial stress, may exacerbate the long-term consequences of exposure to GAS processes through the promotion of central immunomodulatory and oxidative stress.
Highlights
Recent epidemiological, clinical, and preclinical studies suggest that immune responses to pathogens may play a remarkable role in the onset and course of a heterogeneous group of psychiatric disturbances
Our results demonstrate that chronic psychosocial stress, which per se altered the expression of neuroinflammatory markers in the hippocampal and hypothalamic regions, exacerbated the neuroinflammatory alterations induced by experimental Group-A beta-haemolytic streptococcus (GAS) exposures in the same areas
The combined GAS/Stress treatment elicited mitochondrial dysfunctions, brain energy deficit and upregulation of manganese superoxide dismutase (MnSOD), a mitochondrial enzyme playing a major role in modulation of mitochondrial oxidative stress
Summary
Clinical, and preclinical studies suggest that immune responses to pathogens may play a remarkable role in the onset and course of a heterogeneous group of psychiatric disturbances. Several authors proposed that genetically predisposed individuals may develop a series of immune-mediated disturbances, ranging from Paediatric Autoimmune Disorders Associated with Streptococcus (PANDAS) to neuropsychiatric systemic lupus erythematosus and autoimmune encephalopathies [1,2,3,4]. Within this framework, pathogen-directed antibodies are hypothesized to cross-react with a variety of partly identified neuronal antigens for a phenomenon of molecular mimicry, thereby damaging specific brain circuits and result in behavioural abnormalities [5,6]. Sydenham’s chorea (SC) and Tourette’s syndrome (TS) have been proposed to constitute instances of PANDAS [15,16]
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