A dysfunction of CD4^+ T lymphocytes in peripheral immune system of Parkinson's disease model mice

Objective Parkinson's disease(PD),a neurodegenerative disorder,has been reported to be associated with brain neuroinflammation in its pathogenesis.Herein,changes in peripheral immune system were determined to better understand PD pathogenesis and provide possible target for treatment of PD through improvement of immune disorder.Methods l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine(MPTP) was intraperitoneally injected into mice to prepare PD model.Expression levels of pro-inflammatory and anti-inflammatory cytokines and transcription factors of CD4^+ T lymphocyte subsets in spleen and mesenteric lymph nodes and concentrations of the cytokines in serum were examined on day 7 after MPTP injection.Percentages of CD4^+ T lymphocyte subsets were measured by flow cytometry.Results MPTP induced PD-like changes such as motor and behavioral deficits and nigrostriatal impairment.Expression levels of the pro-inflammatory cytokines including interferon(IFN)-γ,interleukin(IL)-2,IL-17 and IL-22,in spleen and mesenteric lymph nodes were upregulated and their concentrations in serum were elevated in PD progression.But,the concentrations of the anti-inflammatory cytokines including IL-4,IL-10 and transforming growth factor(TGF)-β were not altered in the two lymphoid tissues or serum of PD mice.In addition,expression of T-box in T cells(T-bet),the specific transcription factor of helper T(Th) 1 cells,was downregulated,but expression of transcription factor forkhead box p3(Foxp3),the transcription factor of regulatory T(Treg) cells,was upregulated.In support of the results,the numbers of IFN-γ^+-producing CD4^+cells(Th1 cells) were reduced but CD4^+CD25^+ cells(Treg cells) were elevated in both the lymphoid tissues of PD mice.Conclusion PD has a dysfunction of peripheral immune system.It manifests enhancement of proinflammatory response and CD4^+T cell differentiation bias towards Treg cells away from Thl cells.

Interleukin 17A deficiency alleviates neuroinflammation and cognitive impairment in an experimental model of diabetic encephalopathy

Interleukin 17A(IL-17A)was previously shown to be a key pro-inflammatory factor in diabetes mellitus and associated complications.However,the role of IL-17A in diabetic encephalopathy remains poorly understood.In this study,we established a mouse model of diabetic encephalopathy that was deficient in IL-17A by crossing Il17a-/-mice with spontaneously diabetic Ins2^(Akita)(Akita)mice.Blood glucose levels and body weights were monitored from 2-32 weeks of age.When mice were 32 weeks of age,behavioral tests were performed,including a novel object recognition test for assessing short-term memory and learning and a Morris water maze test for evaluating hippocampus-dependent spatial learning and memory.IL-17A levels in the serum,cerebrospinal fluid,and hippocampus were detected with enzyme-linked immunosorbent assays and real-time quantitative polymerase chain reaction.Moreover,proteins related to cognitive dysfunction(amyloid precursor protein,β-amyloid cleavage enzyme 1,p-tau,and tau),apoptosis(caspase-3 and-9),inflammation(inducible nitric oxide synthase and cyclooxygenase 2),and occludin were detected by western blot assays.Pro-inflammatory cytokines including tumor necrosis factor-α,interleukin-1β,and interferon-γin serum and hippocampal tissues were measured by enzyme-linked immunosorbent assays.Microglial activation and hippocampal neuronal apoptosis were detected by immunofluorescent staining.Compared with that in wild-type mice,mice with diabetic encephalopathy had higher IL-17A levels in the serum,cerebrospinal fluid,and hippocampus;downregulation of occludin expression;lower cognitive ability;greater loss of hippocampal neurons;increased microglial activation;and higher expression of inflammatory factors in the serum and hippocampus.IL-17A knockout attenuated the abovementioned changes in mice with diabetic encephalopathy.These findings suggest that IL-17A participates in the pathological process of diabetic encephalopathy.Furthermore,IL-17A deficiency reduces diabetic encephalopathy-mediated neuroinflammation and cognitive defects.These results highlight a role for IL-17A as a mediator of diabetic encephalopathy and potential target for the treatment of cognitive impairment induced by diabetic encephalopathy.