TLR2 and TLR4 in Parkinson's disease pathogenesis: the environment takes a toll on the gut

Abstract

Parkinson's disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD, especially in a subset of people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations of gut homeostasis are hypothesized to contribute to α-synuclein aggregation in enteric neurons, which may spread to the brain over decades and eventually result in the characteristic central nervous system manifestations of PD, including neurodegeneration and motor impairments. However, the mechanisms linking gut disturbances and α-synuclein aggregation are still unclear. A plethora of research indicates that toll-like receptors (TLRs), especially TLR2 and TLR4, are critical mediators of gut homeostasis. Alongside their established role in innate immunity throughout the body, studies are increasingly demonstrating that TLR2 and TLR4 signalling shapes the development and function of the gut and the enteric nervous system. Notably, TLR2 and TLR4 are dysregulated in patients with PD, and may thus be central to early gut dysfunction in PD. To better understand the putative contribution of intestinal TLR2 and TLR4 dysfunction to early α-synuclein aggregation and PD, we critically discuss the role of TLR2 and TLR4 in normal gut function as well as evidence for altered TLR2 and TLR4 signalling in PD, by reviewing clinical, animal model and in vitro research. Growing evidence on the immunological aetiology of α-synuclein aggregation is also discussed, with a focus on the interactions of α-synuclein with TLR2 and TLR4. We propose a conceptual model of PD pathogenesis in which microbial dysbiosis alters the permeability of the intestinal barrier as well as TLR2 and TLR4 signalling, ultimately leading to a positive feedback loop of chronic gut dysfunction promoting α-synuclein aggregation in enteric and vagal neurons. In turn, α-synuclein aggregates may then migrate to the brain via peripheral nerves, such as the vagal nerve, to contribute to neuroinflammation and neurodegeneration typically associated with PD.

Keywords: Gut barrier; Gut homeostasis; Gut-brain axis; Parkinson’s disease; TLR2; TLR4; α-Synuclein.

Fig. 1

Representative schematic of TLR2 and TLR4 distribution in the gut. The Toll-like receptors 2 and 4 (TLR2 and TLR4) are expressed by many different cell populations throughout the gastrointestinal barrier, where they are activated by microbial metabolites and endogenous molecules. TLR2 and TLR4 are expressed by intestinal epithelial cells (IECs) and enteroendocrine cells (EECs) in the epithelial barrier, macrophages, dendritic cells in the submucosa, and smooth muscle cells in the muscular layer of the gut and throughout the enteric nervous system (subepithelial and myenteric, neurons and glia) [37, 81, 125, 126]. In addition to a role in innate immunity, TLR2 and TLR4 in the gut can regulate homeostasis and permeability, and influence motility through their effect on the enteric nervous system [3]. Figure created with Biorender.com

Fig. 2

Representative schematic of TLR-driven gut dysfunction which may contribute to PD. Microbial dysbiosis and pro-inflammatory gut responses can result in a complex positive feedback loop of gut leakiness and inflammation. For example, microbial dysbiosis (1) contributes to the signalling of epithelial toll-like receptors (TLRs) (2), which can result in a leaky gut (3) and further TLR signalling (4) with subsequent cytokine secretion (5) and immune cell activation (6), leading to TLR-associated dysbiosis [3, 4]. Such gut inflammation can alter the enteric nervous system signalling and result in altered motility (7) [135]. It is hypothesised that α-synuclein is secreted by enteric neurons in response to infection to function as an immune-signalling molecule [159], and α-synuclein can directly activate and also change the expression of TLR2 and TLR4, causing further inflammatory responses [57, 58]. Over time, chronic TLR signalling, gut inflammation and sustained α-synuclein secretion may contribute to the formation of insoluble α-synuclein aggregates in the gut, especially if combined with other molecular deficits (e.g., lysosomal dysfunction). This may cause gut dysfunction (e.g. constipation), which is increasingly recognised as a ‘prodromal PD’ phase [20, 36]. Studies demonstrate that insoluble α-synuclein aggregates can spread from the gut to the brain via peripheral nerves (e.g., vagus nerve), where they cause Lewy body pathology in the CNS, neuroinflammation and neurodegeneration, resulting in the characteristic motor impairments of PD [–30]. Figure created with Biorender.com