Neuroinflammation and Parkinson's Disease-From Neurodegeneration to Therapeutic Opportunities

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by a progressive degeneration of dopaminergic neurons (DAn), resulting in severe motor complications. Preclinical and clinical studies have indicated that neuroinflammation can play a role in PD pathophysiology, being associated with its onset and progression. Nevertheless, several key points concerning the neuroinflammatory process in PD remain to be answered. Bearing this in mind, in the present review, we cover the impact of neuroinflammation on PD by exploring the role of inflammatory cells (i.e., microglia and astrocytes) and the interconnections between the brain and the peripheral system. Furthermore, we discuss both the innate and adaptive immune responses regarding PD pathology and explore the gut-brain axis communication and its influence on the progression of the disease.

Keywords: Parkinson’s disease; acute and chronic responses; gut–brain axis; inflammatory cells; neuroinflammation.

Figure 1

Neuroinflammatory response mediated by inflammatory cells and its impact on dopaminergic neurons in Parkinson’s disease (PD). DAMPs released by dying neurons and CCL2, a proinflammatory mediator, released by astrocytes or by misfolded or aggregated proteins (such as α-syn) trigger the initiation of an inflammatory response. Microglia and astrocytes change their morphology and gene expression and secrete several pro- and anti-inflammatory mediators to restore homeostasis. Canonically, activated microglia can be polarized into M1 (mainly proinflammatory cytokines promoting inflammation) or M2 phenotype (especially anti-inflammatory mediators stimulating repair and regeneration, which can be divided into M2a, M2b, or M2c). Similarly, reactive astrocytes acquire A1 and A2 phenotypes. In PD, the dysregulated cytokine release and the vast abundance of M1 and A1 phenotypes contribute to neurotoxicity and neurodegeneration. M1 phenotype is favorably adopted when DAMPs and CCL2 are released. In astrocytes, the presence of α-syn inclusions leads to the production of proinflammatory cytokines. However, this phenotypic and morphological characterization of inflammatory cells was established according to in vitro studies. NRLP3 (inflammasome) can detect aggregated substances (fibrillar α-Syn in microglia or detected by TLR2 receptors) or IL-1β released by microglia, activating the NF-kB pathway and NLRP3 inflammasome, producing proinflammatory cytokines, such as IL-1β and IL-18, which ultimately leads to pyroptosis. Thereby, in in vivo conditions, microglia and astrocytes exhibit wide heterogeneity. Despite the insufficient techniques to precisely identify the participant cells in inflammatory events in PD, their response is affected by the brain region, morphology, phenotype, and function. The inflammatory response occurring in PD mediated by the release of cytokine growth factors and genetic dysregulation produces reactive oxygen species (ROS) and nitric oxide (NO), leading to neurodegeneration of dopaminergic neurons. (Figure generated using BioRender.com (accessed on 1 June 2022)).

Figure 2

A multisystemic view on Parkinson’s disease neuroinflammation: from CNS gliosis to peripheral immune responses. (A) Once neuronal function declines and α-Syn accumulation changes, so will microglia and astrocyte response in PD. The PD brain reaches a chronic inflammatory state characterized by the release of high levels of proinflammatory mediators, continuous degeneration of DAn, and microglia/astrocytic activation. (B) With the loss of BBB functionality (associated with microglia and astrocyte reactivity), the exposure of the brain to blood-derived substances occurs, implying a long-lasting infiltration of immune cells, thus reinforcing the local persistent inflammatory response. (C) Monocytes could be recruited to the inflamed CNS by activated microglia through the secretion of CCL2. The adaptive arm of the immune system will accompany the immune responses, amplifying a Th1-prone profile (secretion of IFN-γ and TNF-α) and high levels of Th17 cells in the systemic circulation and CNS. Alterations in the status of the ENS, such as abnormal α-Syn accumulation in systemic compartments, intestinal inflammation (D), impairments on the intestinal barrier (E), and gut microbial dysbiosis (F), may favor an inflammatory response in the periphery, promote DAn cell death, and amplify chronic CNS inflammation. (Figure generated using BioRender.com (accessed on 1 June 2022)).