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

• Published in: Brain, behavior, & immunity. Health behavior, & immunity. Health, 2022-08, Vol.23, p.100466-100466, Article 100466
• Main Authors: Virenque, Anaïs, Koivisto, Hennariikka, Antila, Salli, Zub, Emma, Rooney, Erin Jane, Miszczuk, Diana, Müller, Adrian, Stoka, Enija, Marchi, Nicola, Alitalo, Kari, Tanila, Heikki, Noe, Francesco Mattia
• Format: Article
• Language: English
• Subjects: Behavioral dysfunctions; Chronic traumatic brain injury; Cortical lesion development; Full Length; Life Sciences; Meningeal lymphatic vessels; Neuroinflammation; Neurons and Cognition
• ISSN: 2666-3546; 2666-3546
• DOI: 10.1016/j.bbih.2022.100466

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. •Developmental deficit in the meningeal lymphatic vessels contributes to sustain the chronic neuroinflammation and represent a susceptibility factor in TBI, despite the lack of a functional phenotype.•Development and progression of TBI-related cortical lesion is not exacerbated by developmental deficit in meningeal lymphatics.•Meningeal lymphatic developmental deficits result in increased neuroinflammation, suggesting a sub-clinical pathological imprint or a vulnerability factor.•Congenital mLV deficit affects the interstitial fluid dynamics and the post-TBI hematoma resolution.