The contribution of the meningeal immune interface to neuroinflammation in traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide, particularly among the elderly, yet our mechanistic understanding of what renders the post-traumatic brain vulnerable to poor outcomes, and susceptible to neurological disease, is incomplete. It is well established that dysregulated and sustained immune responses elicit negative consequences after TBI; however, our understanding of the neuroimmune interface that facilitates crosstalk between central and peripheral immune reservoirs is in its infancy. The meninges serve as the interface between the brain and the immune system, facilitating important bi-directional roles in both healthy and disease settings. It has been previously shown that disruption of this system exacerbates neuroinflammation in age-related neurodegenerative disorders such as Alzheimer's disease; however, we have an incomplete understanding of how the meningeal compartment influences immune responses after TBI. In this manuscript, we will offer a detailed overview of the holistic nature of neuroinflammatory responses in TBI, including hallmark features observed across clinical and animal models. We will highlight the structure and function of the meningeal lymphatic system, including its role in immuno-surveillance and immune responses within the meninges and the brain. We will provide a comprehensive update on our current knowledge of meningeal-derived responses across the spectrum of TBI, and identify new avenues for neuroimmune modulation within the neurotrauma field.

Keywords: Adaptive immunity; Innate immunity; Meninges; Neuroinflammation; TBI.

Fig. 1

Hallmarks of neuroinflammation in Traumatic Brain Injury. Summary of hallmark characteristics that encompass the holistic nature of TBI-induced neuroinflammation. Based on decades of clinical research and mechanistic knowledge gained from the diverse range of injury models, key neuroinflammatory events include: barrier dysfunction, immune triggers and signaling, neural damage or release of soluble factors, neutrophil infiltration, monocyte recruitment, resident CNS microglial and astrocyte responses and activation of T and B cell responses. Importantly, all areas of this neuroinflammatory wheel can be influenced by context dependent factors, and should be considered across the spectrum of the neurotrauma field

Fig. 2

The meningeal neuroimmune interface influencing inflammatory responses in TBI. Simplified schematic of the meningeal interface in healthy and injured settings. In homeostatic conditions (left), border-associated immune cells may synergistically support brain environments through cytokine secretion (IL-4, IL-17), which can directly influence neurons. A network of initial and collecting mLVs expressing Lyve1, drain CSF solutes/molecules to the dCLNs. Immune cell drainage of dendritic and T cells into the dCLNs occurs via chemokine gradients (E.g. CCR7 expressing cells migrating towards its ligands CCL19 and CCL21). TBI (right) causes BBB breakdown and mLV dysfunction, resulting in reduced Lyve⁺ mLVs, and impaired drainage of solutes to the dCLNs. This TBI-induced lymphatic dysfunction and immune activation at the meningeal interface, exacerbates neuroinflammation by resident CNS cells within the brain parenchyma