pubmed.ncbi.nlm.nih.gov

T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson's Disease - PubMed

  • ️Tue Jan 01 2019

Review

T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson's Disease

Javier Campos-Acuña et al. Front Immunol. 2019.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder affecting mainly the dopaminergic neurons of the nigrostriatal pathway, a neuronal circuit involved in the control of movements, thereby the main manifestations correspond to motor impairments. The major molecular hallmark of this disease corresponds to the presence of pathological protein inclusions called Lewy bodies in the midbrain of patients, which have been extensively associated with neurotoxic effects. Importantly, different research groups have demonstrated that CD4+ T-cells infiltrate into the substantia nigra of PD patients and animal models. Moreover, several studies have consistently demonstrated that T-cell deficiency results in a strong attenuation of dopaminergic neurodegeneration in animal models of PD, thus indicating a key role of adaptive immunity in the neurodegenerative process. Recent evidence has shown that CD4+ T-cell response involved in PD patients is directed to oxidised forms of α-synuclein, one of the main constituents of Lewy bodies. On the other hand, most PD patients present a number of non-motor manifestations. Among non-motor manifestations, gastrointestinal dysfunctions result especially important as potential early biomarkers of PD, since they are ubiquitously found among confirmed patients and occur much earlier than motor symptoms. These gastrointestinal dysfunctions include constipation and inflammation of the gut mucosa and the most distinctive pathologic features associated are the loss of neurons of the enteric nervous system and the generation of Lewy bodies in the gut. Moreover, emerging evidence has recently shown a pivotal role of gut microbiota in triggering the development of PD in genetically predisposed individuals. Of note, PD has been positively correlated with inflammatory bowel diseases, a group of disorders involving a T-cell driven inflammation of gut mucosa, which is strongly dependent in the composition of gut microbiota. Here we raised the hypothesis that T-cell driven inflammation, which mediates dopaminergic neurodegeneration in PD, is triggered in the gut mucosa. Accordingly, we discuss how structural components of commensal bacteria or how different mediators produced by gut-microbiota, including short-chain fatty acids and dopamine, may affect the behaviour of T-cells, triggering the development of T-cell responses against Lewy bodies, initially confined to the gut mucosa but later extended to the brain.

Keywords: CD4+ T-cell mediated immunity; Parkinson's disease; gut microbiota; gut-brain axis; neo-antigens; neuroinflammation.

PubMed Disclaimer

Figures

Figure 1
Figure 1

Proposed model by which CD4+ T-cell response involved in Parkinson's disease are triggered in the gut mucosa. (1) In healthy conditions, gut microbiota produces SCFAs and high levels of dopamine. (2) In addition to the gut microbiota, catecholaminergic neurons of the enteric nervous system also contribute to the secretion of high dopamine levels into the gut mucosa and lumen. (3) SCFAs and dopamine stimulate GPR41, GPR43, and GPR109A and low-affinity dopamine receptors (i.e., DRD2), respectively in CD4+ T-cells, favouring their differentiation into Tregs and their suppressive activity, thereby promoting tolerance to food-derived and microbiota-derived antigens. (4) Under some circumstances, such as dysbiosis, some tight junctions components become down-regulated and thereby epithelial layer of gut mucosa might be disrupted. Consequently, some strains of gut microbiota trigger an initial inflammation mediated by innate immune cells, which promote local oxidative stress with the covalent modification of self-proteins. (5) The oxidative environment promotes the generation of α-synuclein inclusions, which impair vesicular secretion by neurons of the enteric nervous system and thereby reduction in dopamine levels. (6) In addition, α-synuclein inclusions are captured by mucosal APCs and presented to naïve CD4+ T-cells specific for Lewy bodies derived antigens. Moreover, α-synuclein inclusions stimulates TLRs in macrophages and dendritic cells, triggering thus inflammation, oxidative stress and thereby further generation of α-synuclein inclusions, which constitutes a vicious cycle of chronic inflammation and generation of Lewy bodies. (7) According to Braak's hypothesis, after a long period of time (years) with chronic inflammation, Lewy bodies generated in the enteric nervous system would be transported by retrograde movement through vagus nerve until reaching the brain stem. (8) Lewy bodies in the brain would stimulate TLRs in microglial cells inducing the production of inflammatory cytokines and thus favouring the permeabilization of the BBB. (9) Inflammatory cytokines coming from peripheral blood circulation would also contribute to BBB permeabilization. In addition, a reduction in SCFAs (i.e., induced by a dysbiosis in gut microbiota) might alter GPR41-signalling in the BBB, thus promoting disassembling of tight junctions and further permeabilization of the BBB. (10) Inflammatory CD4+ T-cells (Th1 and Th17) generated years ago in response to Lewy bodies in the gut mucosa would migrate through the blood and infiltrate the brain (red arrow; this is the main hypothesis raised here). (11) Microglial cells would capture Lewy bodies and subsequently they would present Lewy bodies-derived antigens to Th1 and Th17 infiltrating the brain. Thus, microglial cells would restimulate Lewy body-specific CD4+ T-cells promoting further neuroinflammation and neurodegeneration of the dopaminergic neurons of the nigrostriatal pathway.

Similar articles

Cited by

References

    1. Thomas B. Parkinson's disease: from molecular pathways in disease to therapeutic approaches. Antioxid Redox Signal. (2009) 11:2077–82. 10.1089/ars.2009.2697 - DOI - PMC - PubMed
    1. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature (1997) 388:839–40. 10.1038/42166 - DOI - PubMed
    1. Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, et al. . In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci USA. (2011) 108:4194–9. 10.1073/pnas.1100976108 - DOI - PMC - PubMed
    1. Gonzalez H, Contreras F, Pacheco R. Regulation of the Neurodegenerative Process Associated to Parkinson's Disease by CD4+ T-cells. J Neuroimmune Pharmacol. (2015) 10:561–75. 10.1007/s11481-015-9618-9 - DOI - PubMed
    1. Kim C, Lee SJ. Controlling the mass action of alpha-synuclein in Parkinson's disease. J Neurochem. (2008) 107:303–16. 10.1111/j.1471-4159.2008.05612.x - DOI - PubMed

Publication types

MeSH terms