Significance of developmental meningeal lymphatic dysfunction in experimental post-traumatic injury

Anaïs Virenque; Hennariikka Koivisto; Salli Antila; Emma Zub; Erin Jane Rooney; Diana Miszczuk; Adrian Müller; Enija Stoka; Nicola Marchi; Kari Alitalo; Heikki Tanila; Francesco Mattia Noe

doi:10.1016/j.bbih.2022.100466

Significance of developmental meningeal lymphatic dysfunction in experimental post-traumatic injury

Brain Behav Immun Health. 2022 May 4:23:100466. doi: 10.1016/j.bbih.2022.100466. eCollection 2022 Aug.

Authors

Affiliations

¹ Neuroscience Center, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, 00290, Helsinki, Finland.
² A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210, Kuopio, Finland.
³ Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland.
⁴ Cerebrovascular and Glia Research, Institute of Functional Genomics, University of Montpellier, CNRS, INSERM, Montpellier, France.

Abstract

Understanding the pathological mechanisms unfolding after chronic traumatic brain injury (TBI) could reveal new therapeutic entry points. During the post-TBI sequel, the involvement of cerebrospinal fluid drainage through the meningeal lymphatic vessels was proposed. Here, we used K14-VEGFR3-Ig transgenic mice to analyze whether a developmental dysfunction of meningeal lymphatic vessels modifies post-TBI pathology. To this end, a moderate TBI was delivered by controlled cortical injury over the temporal lobe in male transgenic mice or their littermate controls. We performed MRI and a battery of behavioral tests over time to define the post-TBI trajectories. In vivo analyses were integrated by ex-vivo quantitative and morphometric examinations of the cortical lesion and glial cells. In post-TBI K14-VEGFR3-Ig mice, the recovery from motor deficits was protracted compared to littermates. This outcome is coherent with the observed slower hematoma clearance in transgenic mice during the first two weeks post-TBI. No other genotype-related behavioral differences were observed, and the volume of cortical lesions imaged by MRI in vivo, and confirmed by histology ex-vivo, were comparable in both groups. However, at the cellular level, post-TBI K14-VEGFR3-Ig mice exhibited an increased percentage of activated Iba1 microglia in the hippocampus and auditory cortex, areas that are proximal to the lesion. Although not impacting or modifying the structural brain damage and post-TBI behavior, a pre-existing dysfunction of meningeal lymphatic vessels is associated with morphological microglial activation over time, possibly representing a sub-clinical pathological imprint or a vulnerability factor. Our findings suggest that pre-existing mLV deficits could represent a possible risk factor for the overall outcome of TBI pathology.

Keywords: Behavioral dysfunctions; CCI, Controlled Cortical Injury; Chronic traumatic brain injury; Cortical lesion development; Meningeal lymphatic vessels; Neuroinflammation; TBI, Traumatic Brain Injury; mLV, Meningeal Lymphatic Vessel.