New research published in the journal Neuron identified a previously unrecognized developmental process involving the meningeal lymphatic system and its potential role in social behavior abnormalities associated with autism spectrum disorder. Investigators found that macrophages help refine the dural lymphatic vasculature during postnatal development through coordinated cell death and phagocytosis pathways. In a BTBR mouse model of autism spectrum disorder, failure of this refinement process led to persistence of lymphatic sprouts and was associated with altered social behaviors. The findings also demonstrated that modulation of VEGF-c signaling could restore refinement and improve social interaction in the animal model.1
In this Q&A, Antoine Louveau, PhD, assistant staff member at Cleveland Clinic’s Lerner Research Institute and assistant professor of molecular medicine at Case Western Reserve University School of Medicine, discusses the biologic mechanisms underlying dural lymphatic refinement, the connection between lymphatic development and neurodevelopmental disorders, and how these findings may shape future research into autism spectrum disorder and brain immune regulation. Louveau also reviews the translational implications of targeting VEGF-c–VEGFR3 signaling pathways and the broader significance of meningeal lymphatics in neurologic disease.2
Contemporary Pediatrics: Your study identifies a previously unrecognized role for dural lymphatic refinement during development. What initially led your team to investigate how these lymphatic vessels may influence social behavior and neurodevelopment?
Antoine Louveau, PhD: We and others have been studying the meningeal lymphatic vasculature for over a decade now, and they have been implicated in most neurological disorders, at least in preclinical models. They present a lot of unique characteristics, one of them being their developmental timeline. In preclinical models, they exclusively develop postnatally, which would roughly correspond to the third trimester in humans. At that time, the brain is undergoing major remodeling and maturation steps that are essential for the establishment of normal brain function. These observations led us to dig deeper into how and when these meningeal lymphatic vessels are developing and the impact on how the brain matures, and if, in conditions where brain maturation is altered, there is an associated dysfunction of the meningeal lymphatic vasculature.
Contemporary Pediatrics: The findings suggest that macrophages help shape the developing dural lymphatic network through coordinated cell death and phagocytosis. From a pediatric neurodevelopment perspective, why is this refinement process important during early life?
Louveau: This is a very important question, and our data is only speculating about this process, which will be the purpose of our research in the next couple of years. The brain does not mature in isolation and requires the environment to play its part. From our preclinical studies, what we are finding is that when the meningeal lymphatic vasculature is not refined by the macrophages, there are mild alterations in social behavior. This suggests that proper development of these vessels may have a direct impact on brain maturation, and that a structurally or functionally suboptimal lymphatic vasculature, when the brain needs the most support, may be detrimental. Critically, this appears to be time-restricted, meaning that there is a narrow developmental window during which disruption may have lasting consequences. This has significant implications for understanding neurodevelopmental conditions.
Contemporary Pediatrics: You observed that BTBR mice, a model commonly used in autism spectrum disorder research, failed to properly refine these lymphatic sprouts. What do these findings suggest about the relationship between immune signaling, lymphatic biology, and ASD-related behaviors?
Louveau: I think that these findings highlight that ASD-associated phenotypes may not arise solely from neuronal dysfunction but rather could involve upstream failures in neuroimmune mechanisms that participate in the phenotypic presentation, and that the macrophage-lymphatic crosstalk could be a contributing mechanism rather than a consequence in ASD models. What it highlights the most, in my opinion, is that a neuron that is genetically dysfunctional can be helped to work better by improving its environment and may not need to be targeted directly. Our results are using the BTBR model, which is only a model and will not recapitulate the broad scope of ASD-related behaviors displayed in the human population. A lot more research is required to address the potential impact of lymphatic function in neurodevelopmental disorders in humans.
Contemporary Pediatrics: VEGF-c signaling appeared to play a major role in maintaining these abnormal perisinusal sprouts in BTBR mice. How do you interpret the behavioral improvements seen after modulating the VEGF-c–VEGFR3 pathway, and what questions still need to be answered before considering translational implications?
Louveau: My major interpretation of these results is that we can still target the problem past the developmental window. While the shaping of the meningeal lymphatic by macrophages occurs during a precise timeline, when the problem persists into adulthood, as we see in the BTBR model, we can still target it and improve the associated behavior. In my opinion, there is a lot more work needed before considering translational implications. The major one is to define the patient population that may benefit from this intervention. Neurodevelopmental disorders, and particularly autism spectrum disorders, are not one disease with one specific dysfunctional pathway; it is more of an umbrella of different disorders that converge into a specific behavioral presentation of varying degrees. Our work now aims at first identifying how broadly these lymphatic dysfunctions are present in the realm of neurodevelopmental disease, and second, to develop diagnostic approaches to identify which patients may present dysfunctional lymphatic and, therefore, may benefit from lymphatic targeting therapies.
Contemporary Pediatrics: Pediatricians increasingly recognize the importance of neuroimmune interactions in child development. Based on your findings, what broader message should clinicians take away about the potential role of the meningeal lymphatic system in neurodevelopmental disorders?
Louveau: We are not suggesting that lymphatic dysfunction causes autism or other neurodevelopmental disorders. We are suggesting that the brain does not develop in isolation, and that the meningeal lymphatics and neuroimmune interactions in general may be one of the bridges between early immune health and long-term neurodevelopmental outcomes. We are suggesting that a neuron with genetic dysfunction will be worse if it sits in a dysfunctional environment. We propose for neurodevelopmental disorders, in the clinical setting, to not be approached solely through a neuronal lens and suggest that monitoring the meningeal immune and lymphatic environment deserves serious attention as a contributing layer, which may eventually influence how we think about therapeutic interventions.
