Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic Neurodegeneration
| Autor: | Thomas H. Fox, Zhaoqi Yan, Yudong Liu, Ashley S. Harms, Hao Yu, Yufeng Li, Jessica Buckley, Hongwei Qin, Gordon P. Meares, David G. Standaert, Xinru Li, Etty N. Benveniste |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Neuroprotection Proinflammatory cytokine Rats Sprague-Dawley 03 medical and health sciences Mice 0302 clinical medicine medicine Animals STAT1 Neuroinflammation Janus Kinases Inflammation Microglia biology General Neuroscience Dopaminergic Neurons Macrophages Neurodegeneration JAK-STAT signaling pathway Neurodegenerative Diseases Parkinson Disease Articles medicine.disease Rats Mice Inbred C57BL STAT Transcription Factors 030104 developmental biology medicine.anatomical_structure Neuroprotective Agents Pyrimidines nervous system Immunology Cancer research biology.protein alpha-Synuclein Pyrazoles Janus kinase 030217 neurology & neurosurgery |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 36(18) |
| ISSN: | 1529-2401 |
| Popis: | Parkinson's Disease (PD) is an age-related, chronic neurodegenerative disorder. At present, there are no disease-modifying therapies to prevent PD progression. Activated microglia and neuroinflammation are associated with the pathogenesis and progression of PD. Accumulation of α-synuclein (α-SYN) in the brain is a core feature of PD and leads to microglial activation, inflammatory cytokine/chemokine production, and ultimately to neurodegeneration. Given the importance of the JAK/STAT pathway in activating microglia and inducing cytokine/chemokine expression, we investigated the therapeutic potential of inhibiting the JAK/STAT pathway using the JAK1/2 inhibitor, AZD1480.In vitro, α-SYN exposure activated the JAK/STAT pathway in microglia and macrophages, and treatment with AZD1480 inhibited α-SYN-induced major histocompatibility complex Class II and inflammatory gene expression in microglia and macrophages by reducing STAT1 and STAT3 activation. Forin vivostudies, we used a rat model of PD induced by viral overexpression of α-SYN. AZD1480 treatment inhibited α-SYN-induced neuroinflammation by suppressing microglial activation, macrophage and CD4+T-cell infiltration and production of proinflammatory cytokines/chemokines. Numerous genes involved in cell–cell signaling, nervous system development and function, inflammatory diseases/processes, and neurological diseases are enhanced in the substantia nigra of rats with α-SYN overexpression, and inhibited upon treatment with AZD1480. Importantly, inhibition of the JAK/STAT pathway prevented the degeneration of dopaminergic neuronsin vivo. These results indicate that inhibiting the JAK/STAT pathway can prevent neuroinflammation and neurodegeneration by suppressing activation of innate and adaptive immune responses to α-SYN. Furthermore, this suggests the feasibility of targeting the JAK/STAT pathway as a neuroprotective therapy for neurodegenerative diseases.SIGNIFICANCE STATEMENTα-SYN plays a central role in the pathophysiology of PD through initiation of neuroinflammatory responses. Using an α-SYN overexpression PD model, we demonstrate a beneficial therapeutic effect of AZD1480, a specific inhibitor of JAK1/2, in suppressing neuroinflammation and neurodegeneration. Our findings document that inhibition of the JAK/STAT pathway influences both innate and adaptive immune responses by suppressing α-SYN-induced microglia and macrophage activation and CD4+T-cell recruitment into the CNS, ultimately suppressing neurodegeneration. These findings are the first documentation that suppression of the JAK/STAT pathway disrupts the circuitry of neuroinflammation and neurodegeneration, thus attenuating PD pathogenesis. JAK inhibitors may be a viable therapeutic option for the treatment of PD patients. |
| Databáze: | OpenAIRE |
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