Resolution of inflammation is impaired in patients with Parkinson’s disease and is rescued by specialized pro-resolving lipid mediator Resolvin D1

Uncontrolled or unresolved neuroinflammation is associated with many widely occurring diseases such as Parkinson’s disease (PD), which is the second commonest neurodegenerative disorder of the central nervous system characterized by loss of dopaminergic (DA) neurons in the Substantia nigra pars compacta (SNpc), accumulation of misfolded neuronal α-synuclein (α-syn) inclusions and neuroinflammation. In addition to traditional pathological mechanisms, peripheral inflammation has been found to play a critical role in disease progression. Recent studies suggest that neuroinflammation could be due to a failure in resolving inflammation, the resolution of which is mediated by a newly characterized pathway that involves omega-3 derived specialized pro-resolving lipid mediators (SPMs), that include resolvins. By means of targeted lipidomics we found elevated values of pro-inflammatory mediators, such as prostaglandins (PGs) in both plasma and cerebrospinal fluid (CSF) of PD patients, those were associated to disease severity. Since RvD1 was the key SPM to be significantly induced in both tissues at the onset of disease and then progressively lost along disease course, by means of high dimensional flow cytometry we then deeply investigated which immune populations might be involved in such RvD1-associated impairment, and we found that both innate myeloid cells and lymphoid cells as well as adaptive lymphoid cells showed differential expression profiles of both RvD1 enzymes and receptors according to the disease stage. Next, in order to exploit the therapeutic potential of RvD1, we used a rat model of PD overexpressing human α-synuclein (SNCA+/+) and treated with RvD1 methyl ester, starting at an early stage of the disease (2 months old) and until the symptomatic phase (12 months old). Using high dimensional flow cytometry, we found that RvD1 was able to strongly reduce the inflammatory responses of peripheral blood T lymphocytes and to block their infiltration in the substantia nigra and striatum, two key pathological brain areas involved in PD pathogenesis. In conclusion, we identified significant defects in the resolution of inflammation pathway in PD patients, which could be crucial for the worsening of the pathological condition, allowing the inflammation to progress towards chronicity. Furthermore, we propose RvD1 as a potential therapeutic candidate to blunt neuroinflammation and to use it to design potential disease-modifying treatment for PD based on targeting specific immune cells.