Abstract
Experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), a demyelinating autoimmune disease caused by the infiltration of a harmful autoreactive Th1 and Th17 cells. To mitigate MS, which is impossible to cure with medication only, immunomodulatory interventions that prevent Th17 cell activation are ideal. The objective of the present study was to analyze the effect of Toxoplasma gondii infection on the onset of EAE. Our results found that Toxoplasma gondii infection in the brain increases SOCS3 expression and decreases the phosphorylation of STAT3, resulting in reducing IL-17A and IL-23, which suppress the differentiation and expansion of pathogenic Th17 cells, an important factor in MS development. These immune responses resulted in a reduction in the clinical scoring of EAE induced by myelin oligodendrocyte glycoprotein 35–55 immunization. In the EAE group with T. gondii infection (Tg + EAE group), Th17-related immune responses that exacerbate the onset of EAE were reduced compared to those in the EAE group. This study suggests that the alleviation of EAE after T. gondii infection is regulated in a SOCS3/STAT3/IL-17A/blood–brain barrier integrity-dependent manner. Although parasite infection would not be permitted for MS treatment, this study using T. gondii infection identified potential targets that contribute to disease attenuation.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and the most common inflammatory neurological disease in young adults [5, 21]
Given that IL-27 did not increase in the EAE group, these results suggest that T. gondii infection induces the increase in suppressor of cytokine signaling 3 (SOCS3) and IL-27 in both the brain and spinal cord, and it is certain that the increase in SOCS3 and IL-27 in the Tg + EAE group is due to T. gondii infection
Quantitative analysis of tissue fluorescence intensity (FI) showed that the expression of p-STAT3 was increased only in the EAE group but not in the Tg or the Tg + EAE group (p < 0.05, Fig. 8e). These results suggest that the increase in SOCS3 after T. gondii infection resulted in a decrease in STAT3 phosphorylation and simultaneously decreased IL-6/Janus kinase (JAK)/STAT3 pathway activity
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and the most common inflammatory neurological disease in young adults [5, 21]. This study had some limitations such as the assessment of a small study population ( 115 patients and 60 age- and sex-matched healthy subjects) and the presence of specific IgG antibodies against T. gondii, the authors suggested that further studies were required to establish the protective role of parasitic infections in MS, such as the hypothesized immunomodulatory effects of parasitic infections on autoimmune diseases [10] In this regard, our previous study demonstrated the favorable effects of immunosuppression induced by T. gondii infection on the pathogenesis and progression of Alzheimer’s disease (AD) in Tg2576 AD mice [7]. Because IFN-γ signals upregulate inducible nitric oxide synthase, IFN-γ activation in the brain causes tissue injury and neurodegeneration via the production of toxic metabolites, including nitric oxide (NO) [6, 20] In this case, T. gondii modulates host immunity, leading to prolonged parasitic survival without an excessive inflammatory response in the CNS, through increases in SOCS1 and Arg and by reductions in phosphorylated STAT1 (P-STAT1) and NO [6]. Since the expression of those genes strongly suggests the possibility of autoimmune disease suppression, we studied the relationship with experimental autoimmune encephalomyelitis (EAE)
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