Induction of Adaptive Immunity Leads to Nigrostriatal Disease Progression in MPTP Mouse Model of Parkinson's Disease.

Abstract

Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model is the most widely used animal model for Parkinson's disease (PD), it is known that nigrostriatal pathologies do not persist in the acute MPTP mouse model. This study highlights the importance of adaptive immunity in driving persistent and progressive disease in acute MPTP-intoxicated mice. Although marked infiltration of T cells into the nigra was found on 1 d of MPTP insult, T cell infiltration decreased afterward, becoming normal on 30 d of insult. Interestingly, twice-weekly supplementation of RANTES and eotaxin, chemokines that are involved in T cell trafficking, drove continuous T cell infiltration to the nigra and incessant glial inflammation. Supplementation of RANTES and eotaxin was also associated with the induction of nigral α-synuclein pathology, persistent loss of dopaminergic neurons and striatal neurotransmitters, and continuous impairment of motor functions in MPTP-intoxicated mice. In contrast, supplementation of TNF-α and IL-1β, widely studied proinflammatory cytokines, did not induce persistent disease in MPTP-insulted mice. Our results suggest that induction of adaptive immunity by RANTES and eotaxin could hold the key for driving persistent nigrostriatal pathologies in the MPTP mouse model, and that targeting these factors may halt disease progression in PD patients.

• Authors: Goutam Chandra, Avik Roy, Suresh B Rangasamy, Kalipada Pahan
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 198 Issue 11 Pg. 4312-4326 (06 01 2017) ISSN: 1550-6606 [Electronic] United States
• PMID: 28446566 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 by The American Association of Immunologists, Inc.

Chemical References

• Ccl11 protein, mouse
• Ccl5 protein, mouse
• Chemokine CCL11
• Chemokine CCL5
• Interleukin-1beta
• Tumor Necrosis Factor-alpha

Topics

• Acute Disease
• Adaptive Immunity
• Animals
• Chemokine CCL11 (administration & dosage)
• Chemokine CCL5 (administration & dosage)
• Disease Progression
• Inflammation
• Interleukin-1beta (administration & dosage)
• MPTP Poisoning (immunology, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Substantia Nigra (immunology, pathology)
• Tumor Necrosis Factor-alpha (administration & dosage)