Glymphatic system: a gateway for neuroinflammation

Abstract

The glymphatic system is a relatively recently identified fluid exchange and transport system in the brain. Accumulating evidence indicates that glymphatic function is impaired not only in central nervous system disorders but also in systemic diseases. Systemic diseases can trigger the inflammatory responses in the central nervous system, occasionally leading to sustained inflammation and functional disturbance of the central nervous system. This review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system inflammation. In addition, we discuss the hypothesis that disease conditions initially associated with peripheral inflammation overwhelm the performance of the glymphatic system, thereby triggering central nervous system dysfunction, chronic neuroinflammation, and neurodegeneration. Future research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.

Figure 1

The glymphatic system and fluid transport. In the glymphatic system, the CSF flows from the subarachnoid space into the perivascular space of the penetrating cerebral arteries. With the support of AQP4 on the astrocyte endfeet, fluid and waste matters exchanged between the CSF and the ISF are eventually diverted into the perivenous space. When AQP4 polarization is lost, i.e., AQP4 is no longer densely expressed in the astrocyte endfeet but soma, and its role in supporting fluid exchange in the glymphatic system is greatly diminished. In such circumstances, the glymphatic ability to transport physiological molecules or substances, as well as remove interstitial waste and proteins from the brain, is compromised. Created with Adobe Illustrator. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). AQP4: Aquaporin-4; CSF: cerebrospinal fluid; ISF: interstitial fluid.

Figure 2

Glymphatic dysfunction serves as a mechanism contributing to the chronicity of inflammation. Circulating inflammatory signals from the systemic disease are mediated by IL-1, TNF-α, and TNFR1 as these inflammatory cells cross the vascular endothelium into the perivascular space. Matrix metalloproteinases and chemokines allow immune cells to cross from the perivascular space into the brain parenchyma. This aforementioned process effectively facilitates the transmission of immune signals from the circulation to the brain parenchyma. Furthermore, immune cells that accumulate in the perivascular space can secrete inflammatory factors such as IL-23 to further amplify local inflammation. It is plausible that these immune cells and cytokines that accumulate in the perivascular space serve as instigating factors in glymphatic dysfunction. Consequently, impaired glymphatic function results in reduced clearance of inflammatory mediators within the brain. As a result, the severity of neuroinflammation increases and the duration is prolonged, ultimately developing into chronic neuroinflammation. Created with Adobe Illustrator. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). AQP4: Aquaporin-4; CCL2: C-C motif chemokine ligand 2; CSF: cerebrospinal fluid; CXCL: C-X-C motif chemokine ligand; IL: interleukin; MMP: matrix metalloenzymes; TNFR1: tumor necrosis factor receptor-1; TNF-α: tumor necrosis factor-α.

Figure 3

Vicious cycle of glymphatic dysfunction and neuroinflammation. A model illustrates the potential for reciprocal interaction and exacerbation between glymphatic dysfunction and neuroinflammation. The glymphatic dysfunction contributes to the deterioration of neuroinflammation by promoting the accumulation of inflammatory mediators and activating glial cells. Additionally, neuroinflammation further impairs the function of the glymphatic system through mechanisms including the generation of neutrophil extracellular traps and enlargement of the perivascular space. This hypothesis may offer insights into the persistent nature of neuroinflammation and neurodegeneration. Created with Adobe Illustrator. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). ISF: Interstitial fluid; NLRP3: nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3.