Neuro-Immune Hemostasis: Homeostasis and Diseases in the Central Nervous System

Abstract

Coagulation and the immune system interact in several physiological and pathological conditions, including tissue repair, host defense, and homeostatic maintenance. This network plays a key role in diseases of the central nervous system (CNS) by involving several cells (CNS resident cells, platelets, endothelium, and leukocytes) and molecular pathways (protease activity, complement factors, platelet granule content). Endothelial damage prompts platelet activation and the coagulation cascade as the first physiological step to support the rescue of damaged tissues, a flawed rescuing system ultimately producing neuroinflammation. Leukocytes, platelets, and endothelial cells are sensitive to the damage and indeed can release or respond to chemokines and cytokines (platelet factor 4, CXCL4, TNF, interleukins), and growth factors (including platelet-derived growth factor, vascular endothelial growth factor, and brain-derived neurotrophic factor) with platelet activation, change in capillary permeability, migration or differentiation of leukocytes. Thrombin, plasmin, activated complement factors and matrix metalloproteinase-1 (MMP-1), furthermore, activate intracellular transduction through complement or protease-activated receptors. Impairment of the neuro-immune hemostasis network induces acute or chronic CNS pathologies related to the neurovascular unit, either directly or by the systemic activation of its main steps. Neurons, glial cells (astrocytes and microglia) and the extracellular matrix play a crucial function in a “tetrapartite” synaptic model. Taking into account the neurovascular unit, in this review we thoroughly analyzed the influence of neuro-immune hemostasis on these five elements acting as a functional unit (“pentapartite” synapse) in the adaptive and maladaptive plasticity and discuss the relevance of these events in inflammatory, cerebrovascular, Alzheimer, neoplastic and psychiatric diseases. Finally, based on the solid reviewed data, we hypothesize a model of neuro-immune hemostatic network based on protein–protein interactions. In addition, we propose that, to better understand and favor the maintenance of adaptive plasticity, it would be useful to construct predictive molecular models, able to enlighten the regulating logic of the complex molecular network, which belongs to different cellular domains. A modeling approach would help to define how nodes of the network interact with basic cellular functions, such as mitochondrial metabolism, autophagy or apoptosis. It is expected that dynamic systems biology models might help to elucidate the fine structure of molecular events generated by blood coagulation and neuro-immune responses in several CNS diseases, thereby opening the way to more effective treatments.

The Mast Cell Is an Early Activator of Lipopolysaccharide-Induced Neuroinflammation and Blood-Brain Barrier Dysfunction in the Hippocampus

“…CNS diseases affect millions of people and impose psychological burdens on their families with long-term sequelae, high rates of hospitalizations, and ongoing cognitive impairments [31]. It is widely believed that disturbances of CNS homeostasis, including injury, ischemia, infection, and neurodegenerative diseases, evoke neuroinflammatory responses in the brain [32].…”

Neurons, Glia, Extracellular Matrix and Neurovascular Unit: A Systems Biology Approach to the Complexity of Synaptic Plasticity in Health and Disease

“…Among the molecules acting as gliotransmitters, glutamate, GABA, D-serine, ATP and adenosine have been shown to control the basal tone and threshold of synaptic activity, surpassing the all-or-none law of the action potential-mediated neurotransmitters release [77,78]. Finally, astrocytes participate in the secretion of proNTs and their processing in the ECM [14]. Moreover, NTs synthesized in neurons and secreted as proNTs into the ECM can be rapidly internalized into perineuronal astrocytes via p75 mediated endocytosis.…”

“…Microglia can rapidly sense differences and homeostatic perturbations by scanning other cells (astrocytes and neurons) and the brain ECM ( Figure 1) [108], and surveying the environment for pathogens and autologous debris (phagocytic function) ( Figure 2) as the first cellular line in the innate immune response [14,[109][110][111]. In the last scenario, microglia can mediate the loosening of BBB and the secondary immune reaction [112].…”

“…The resilience of CNS and synaptic plasticity in the critical period of development and in the adult brain depends on specialized forms of ECM, such as the interstitial matrix, the perineural nets (PNNs) and the basement membrane. Particularly, this last structure is important for the integration of the neurovascular unit (NVU) to obtain an overall model that could be used as a start point for a systems biology-based approach [14]. The implementation of protein-protein interactions involving all the cellular and non-cellular elements of the system can help the building of hub-spoke network maps [14] to design further experiments with translational purposes.…”

“…Particularly, this last structure is important for the integration of the neurovascular unit (NVU) to obtain an overall model that could be used as a start point for a systems biology-based approach [14]. The implementation of protein-protein interactions involving all the cellular and non-cellular elements of the system can help the building of hub-spoke network maps [14] to design further experiments with translational purposes. Indeed, the ECM is involved in the bidirectional exchange of nutrients and metabolic products between CNS and systemic circulation.…”