Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

Abstract

Traumatic brain injury (TBI) has emerged as a leading cause of death and disability. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the meningeal lymphatic system was identified as a critical mediator of drainage from the CNS. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts meningeal lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. Here we demonstrate that even mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that can last out to at least two weeks post-injury. To investigate a mechanism behind impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics, as increased ICP commonly occurs in TBI. We demonstrate that increased ICP is capable of provoking meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. These findings provide new insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease

“…When meningeal lymphatics are ligated in mice, it worsens the disease phenotype as a result of meningeal lymphatic dysfunction (Zou et al, 2019). Likewise, meningeal lymphatic disruption is accompanied by worsened outcomes in different models of experimental stroke (Chen et al, 2019;Yanev et al, 2020), and in a brain concussion model, where they seem to regulate the extent of edema, the degree of microglial activation, and overall neuronal degeneration (Bolte et al, 2019). Together, these findings suggest that meningeal lymphatics may be a viable therapeutic target for neurological disorders associated with protein accumulation/aggregation.…”

The utilization of small non‐mammals in traumatic brain injury research: A systematic review

“…On the other hand, the mammalian TBI model is more advanced in its robust research background focusing on the mechanism and important biomarkers. 117,[163][164][165][166][167][168] In addition to that, non-mammalian research has not conducted any research on inducing stem cell for brain injury as been conducted previously in this study with mammalian model. 169,170 Indeed, one of the study showed successful xenotransplantation of human iPSC-derived NSCs and isogenic neural cell progenies in a mouse model.…”

The role of innate immunity in Alzheimer's disease

“…264,265 For instance, TBI has recently been shown to compromise meningeal lymphatic function, namely its ability to drain inflammatory byproducts to lymph nodes following injury. 266 Interestingly, meningeal lymphatic drainage defects are known to significantly increase meningeal Aβ load and to provoke memory deficits in 5xFAD AD mice. 265 Therefore, meningeal lymphatic dysfunction may provide another explanation for the association between AD pathogenesis and brain injury, with promising clinical implications that require further investigation.…”