Inflammasome Activation in Parkinson’s Disease

Abstract

Chronic sterile inflammation and persistent immune activation is a prominent pathological feature of Parkinson’s disease (PD). Inflammasomes are multi-protein intracellular signaling complexes which orchestrate inflammatory responses in immune cells to a diverse range of pathogens and host-derived signals. Widespread inflammasome activation is evident in PD patients at the sites of dopaminergic degeneration as well as in blood samples and mucosal biopsies. Inflammasome activation in the nigrostriatal system is also a common pathological feature in both neurotoxicant and α-synuclein models of PD where dopaminergic degeneration occurs through distinct mechanisms. The NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome has been shown to be the primary driver of inflammatory neurotoxicity in PD and other neurodegenerative diseases. Chronic NLRP3 inflammasome activation is triggered by pathogenic misfolded α-synuclein aggregates which accumulate and spread over the disease course in PD. Converging lines of evidence suggest that blocking inflammasome activation could be a promising therapeutic strategy for disease modification, with both NLRP3 knockout mice and CNS-permeable pharmacological inhibitors providing robust neuroprotection in multiple PD models. This review summarizes the current evidence and knowledge gaps around inflammasome activation in PD, the pathological mechanisms by which persistent inflammasome activation can drive dopaminergic degeneration and the therapeutic opportunities for disease modification using NLRP3 inhibitors.

Inflammatory CSF profiles and longitudinal development of cognitive decline in sporadic and GBA-associated PD

“…In-vivo and in-vitro experiments show an up-regulation of SCF in neurons of injured brain tissue paralleled by neural stem/progenitor cell migration highlighting that SCF is involved in self-renewal and cell survival 31 . A central role in maintaining chronic in ammation upon αsynuclein aggregation and cell death is the bi-directional loop between activated microglia and activated in ammasome 32 . Both further induce secretion of in ammatory cytokines such as Interleukin-1 beta, Interleukin-6 and MCP-1.…”

The Role of Epigenetics in Neuroinflammatory-Driven Diseases

“…Together with this, reactive microglia are characterized by a proinflammatory secretome depicted by release of cytokines, i.e., IL-1β, IL-6, TNF, with chemokines and bioactive lipids eventually reinforcing the already inflamed microenvironment. As a result, such a cellular state might impair the blood–brain barrier (BBB), eventually resulting in an increased leukocyte infiltration further boosting the local inflammatory response [ 137 ]. Supporting this scenario, two independent studies showed an increase in cellular death rate of cultured dopaminergic neurons upon exposure to a conditioned media derived either from M1-like microglia and lipopolysaccharide (LPS)-treated glial cells [ 138 , 139 ].…”

Linking Immune Activation and Parkinson’s Disease

“…PD is influenced by many factors including a mix of immunogenetics and the environment, such as infection history. In recent years, increasing evidence suggests an association with autoimmune conditions, with the involvement of the immune system or its aberrant responses in patients and various experimental models [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. In this special issue, our authors highlight the latest research breakthroughs on the links between immune activation and neuroinflammation and PD, and discuss the challenges and novel therapeutic strategies targeting the immune system ISSN 1877-7171/$35.00 © 2022 -IOS Press.…”

“…Understanding how neurons respond to the early stages of inflammation will provide crucial clues for potential early intervention. In this context, the demonstration of inflammasome activation in human PD biosamples and also at sites of dopaminergic degeneration suggest that these multi-protein intracellular signaling complexes (part of the innate immune system) play an important role in neuroinflammatory responses to pathogens and toxic insults [12]. It is interesting to note that chronic NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome activation can be facilitated by pathogenic misfolded alpha synuclein aggregates, while targeting NLRP3 inflammasome activation is protective in experimental animal models [13].…”

“…In summary, multiple independent studies in clinical and pre-clinical models have provided corroborative evidence of the involvement of central and peripheral immune and inflammatory processes in PD [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Our knowledge of how the immune system contributes to PD pathogenesis is constantly evolving with increasing evidence for a role of several genes and susceptibility loci [1,2].…”