Interleukin 4-induced neuroprotection and regulation of microglia activation as a therapeutic approach in the MPTP model of Parkinson's disease

Bj?rn Spittau

doi:10.4103/1673-5374.215250

摘要：Parkinson's disease (PD) has been described as one of the most common neurodegenerative diseases affecting up to 2% of the worldwide population over 60 years of age. The hallmarks of PD are progressive loss of midbrain dopaminergic (mDA) neurons and a decrease in striatal dopamine levels, which result in typ-ical clinical motor symptoms such as akinesia, resting tremor, rigidity, and gait impairments. Although the causes for PD are only partially understood and seem to be very heterogeneous, one of the common phenomenons observed in toxin-based an-imal models of PD as well as PD patients is a microglia-driven neuroinflammatory response, which is at least in part responsi-ble for exacerbation of neuronal loss and worsening of clinical symptoms (Machado et al., 2016). As recently summarized by these authors, degeneration of mDA neurons results in reduced neuron-microglia communication and the release of intracellu-lar components from dying neurons further triggers the activa-tion of microglia located in close proximity to challenged mDA neurons. Upon activation, microglia increase expression and re-lease of several inflammatory factors that subsequently compro-mise stressed mDA neurons, thus, fostering the progressive na-ture of PD (Figure 1). Next to microglia-mediated neurotoxicity, aging is one of the major risk factors to develop PD. Interestingly, aging further affects microglia as well as their functional states and the impact of age-dependent microglia changes on neurode-generation is currently extensively studied. Microglia in the aged central nervous system (CNS) have been described to express higher levels of inflammatory markers such as tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) or interleukin 6 (IL-6) and have been further shown to react to inflammatory stimuli with a stronger and prolonged response. This phenomenon is referred to as microglia priming and recent studies have demon-strated that aged and primed microglia promote enhanced neu-rotoxic effects in animal models of PD (Spittau, 2017). However, depending on the activating stimuli, microglia reactions are also able to promote neuroprotection and neuroregeneration. Among the factors inducing a protective microglia activation phenotype, interleukin 4 (IL-4) has been demonstrated to shift microglia ac-tivation towards a regenerative and anti-inflammatory phenotype in vitro andin vivo (Zhou et al., 2012; Casella et al., 2016).