This is a preview of subscription content, log in to check access. Andersson P, Perry V, Gordon S The kinetics and morphological characteristics of the macrophagemicroglial response to kainic acid-induced neuronal degeneration. Springer, New York Google Scholar. Chavan S, Tracey K Neurophysiologic reflex mechanisms in immunology. In: Paul W ed Fundamental immunology, 7th edn. Gold P The organization of the stress system and its dysregulation in depressive illness. Gonzalez H, Elgueta D, Montoya A, Pacheco R Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases.
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The complexity of the neuro-immune system interaction starts at the level of the neurovascular unit. This structure is composed by the blood—brain barrier BBB elements endothelial cells, pericytes and the astrocytic foot endings on the one side, and neurons, glia and extracellular matrix ECM on the other side Muoio et al.
All together, these elements neurons, glia, and ECM constitute what has been well-described as the tetrapartite synapse Dityatev and Rusakov, ; Tsilibary et al. This complex structure accounts for the immune privileged properties of the brain and of the spinal cord which has its own blood—barrier BSCB Bartanusz et al. The efficacy of the barrier is based on the innate immune properties of resident cells neurons and glia , which interact with pathogens, endogenous e.
The resiliency of the system strictly depends on a variety of proteins that have been grouped for their functional role of neuro-immune regulators NIReg and are expressed on both glial cells and neurons Bedoui et al. Molecular pathways of the neuro-immune hemostasis model. The canonical activation of PAR1, together with tyrosine kinase receptor activation and the fibrin deposition blue pathway , accelerate maladaptive cellular changes. Thrombin, a crucial protein in this network, has been reported to affect the behavior of CNS resident cells, such as neurons Olianas et al.
Thrombin not complexed with thrombomodulin , FXa, plasmin, and matrix metalloproteinases-1 MMP-1 canonically activate PAR1 on cell surface, unmasking the tethered ligand with a proteolytic cleavage and causing its internalization Ye et al. PAR2, instead, can be activated by low-concentration of trypsin. Indeed, it can act as a cofactor for other PARs to form heterodimers and amplify the variety of intracellular transduction systems Arachiche et al.
Non-canonical cleavage by aPC also activates PAR1 biased agonism and trigger a different intracellular pathway Figure 1. NIReg also include serpins and thrombomodulin, which are able to reduce the potential neurotoxicity of thrombin, mainly mediated through tethered ligand activation of PAR1 signaling Buisson et al. The lipopolysaccharide LPS , furthermore, stimulates the expression of coagulation and inflammation factors in the hippocampal microglia, but a sharp reduction of both inflammatory and coagulation factors occurs when the thrombin-mediated signal is inhibited Shavit Stein et al.
Definitely, based on relevance of the neurovascular unit in modulating neuro-immune hemostasis and neuroinflammation, we propose that the neurovascular complex can be associated with the tetrapartite synapse to form an ultimately unified pentapartite synaptic model Figure 2. This model might better represent the complex and robust interplay between cellular and molecular pathways of coagulation and the immune system, as reported by in vitro or in vivo studies Thornton et al.
The analysis of the state of the art in this field can partly reveal the pathophysiology of neuro-inflammatory and neurodegenerative diseases, such as multiple sclerosis MS , cerebrovascular, Alzheimer, neoplastic and psychiatric diseases. Multiple sclerosis is a demyelinating autoimmune inflammatory disease affecting the CNS white matter. It lacks a commonly recognized causative agent idiopathic , and the multifactorial interactions between environment and genetics are not fully elucidated Sawcer et al.
Though the pathophysiology of MS remains unknown, there is morphological evidence of its inflammatory origin and of the resulting neurodegeneration, moreover, therapies targeting the inflammasome modify the progression of the disease mainly the relapsing-remitting phenotype Dahdaleh et al. On the base of the clinical observation and the progression, MS can be classified into two forms, relapsing-remitting and progressive primary or secondary Lublin and Reingold, Inflammation with relatively preserved cell viability seems to be the hallmark of relapsing-remitting early stages, is characterized by clinical features that can affect the motor system particularly the pyramidal tract or non-motor areas, depending on which part of the CNS is affected by the demyelination.
Every relapse is followed by a spontaneous partial remission, ameliorated by early therapy Lublin and Reingold, , while the progressive forms, either the primary or the evolution of the initially relapsing-remitting MS secondary , are characterized by a continuous neurodegeneration with almost ineffective therapy on its progression Lublin and Reingold, ; Feinstein et al.
Which is the key to understand the failure of the immune system has been long debated.
As discussed above, the neurovascular unit should prevent inappropriate migration of leukocytes from the bloodstream and protect the CNS. The Trojan horse that could cause the BBB failure and allow the specific T-cells diapedesis has not been identified yet, but a putative role could be assigned to platelets activation and fibrin depots in the CNS and other tissues Hultman et al.
These cellular and protein aggregates can be produced by a minimal vascular damage or venous stasis, and their pathological accumulation could produce a non-diffusible and localized signal to mediate lymphocyte T helper Th 1 migration and myelin targeting Ryu et al. This hypothesis is supported by the evidence of the occurrence of fibrinogen in myelinated areas that correlates with T-cells invasion and IL mediated Th1 differentiation, macrophage activation through CCL2 and CXCL10 and following demyelination Lodygin et al. Furthermore, in the autoimmune encephalomyelitis model EAE it has been shown that depletion of fibrinogen blocks T-cell activation, accelerating the coagulopathy-mediated pathway Akassoglou et al.
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Furthermore, mediators from platelet granules include growth factors i. Hence, the initial vascular damage activates platelets and converts fibrinogen. Platelets phenotype, at this point, is characterized by low selectin expression and low-rate degranulation. The acute inflammatory response is not produced only by the active degranulation; the expression of other proteins is needed to activate the inflammasome.
Moreover, the corresponding receptor IL1R is expressed on the platelet surface, allowing an autocrine self-sustaining feedback Brown et al. Cellular model of a pentapartite synapse. Common cellular pathways and cell-specific role within the neuro-immune hemostasis network. During later stages, the process is self-sustaining and platelets change their phenotype, express a higher level of selectins and adhere to T-cells or to antigen presenting cells, forming aggregates Starossom et al.
The pivotal role of the molecular components of the coagulation cascade is confirmed by the protective action in the EAE model exerted by the administration of both warfarin and the non-vitamin K antagonist oral anticoagulant NOAC rivaroxaban direct inhibitor of FXa Stolz et al.
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Thrombin can interrupt BBB integrity through PAR1 signaling; however, warfarin effect seems to be greater than rivaroxaban, probably resulting for the interactions with other proteins of the coagulation pathway, such as FVII Coughlin, , The lysis of fibrin, furthermore, should inhibit microglia activation via CD11b part of CR3, encoded by ITGAM gene and produce a similar beneficial effect in the EAE model without the possible detrimental side effect of warfarin due to the inhibition of the aPC endothelial protective functions Adams et al.
The protective role of aPC, however, is not a linear process; it has been shown that the anticoagulant and the intracellular signaling function of aPC are both essential to exert neuroprotection. This seems apparently controversial, but it can be explained because reduced endogenous aPC can induce early leukocyte infiltration due to BBB instability; at the same time, it increases CD11b positive elements, interfering with T-cells differentiation, thus reducing disease progression Alabanza et al.
Reduction of aPC is effective only if it is induced before the disease onset Alabanza et al. As the aforementioned CD11b positive elements confirm, the complement system pathway is a prominent component of the immune response and is entirely involved in inflammatory autoimmune disease at various levels.
The system plays a pivotal role in essentially all immune-mediated processes, and it made difficult, although intriguing, designing drugs targeting its components. Complement proteins can act through three main activation pathway: classical, lectin and alternative pathway, all at the end forming the MAC complex with the elimination of target cells Horstman et al. Detrimental effects of complement interference can be overcome through inhibition at the lower level of complement activation cascade e. This strategy may reduce detrimental inflammation without affecting previous signaling steps.
NMO with dominant involvement of optic nerves and spinal cord has been previously considered as a variant of MS. Nowadays, it is considered a distinct disease Trebst et al. Moreover, the efficacy of thrombolysis and the current guidelines for the management of acute ischemic stroke AIS have rapidly reduced the acute mortality rate. Nowadays, the main social burdens and future challenges concern prolonged hospitalization, ineffective rehabilitation program, disability, and the epileptic sequelae Szaflarski et al.
Studies on human platelet activation focused on platelet ultrastructure and plasma levels of PF4, thrombin—antithrombin complex, fibrinogen and other biomarkers in patients with AIS, and during the chronic phase or with atherosclerosis without stroke compared to healthy subjects Kurabayashi et al. Data are compatible with platelet pre-activation in atherosclerotic patients, similar but lower compared to patients with AIS or chronic phase. Pre-activated platelets showed a higher density of pseudopods and vacuoles Kurabayashi et al.
The endothelial damage reported in atherosclerosis, combined with a pre-activated state of platelets, is the most plausible factor for inflammatory-mediated CNS damage that accelerates the major hypoxic injury.
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Astrocytes and other glial cells play a key role in the rearrangement of the neurovascular unit. The CCL22 receptor CCR4, expressed on Th2 cells can shift the inflammatory response toward an adaptive deregulation, suppressing Th1-polarized response. This is supportive for a protective immune response, initiated during the acute ischemic event and lasting for some time Theodorou et al.
Microglia express C1q during transient ischemic attack and deposits of C3d and C9 have been reported on neuronal cells after traumatic concussion Pasinetti et al. Depletion of the complement factor, C1q deficiency, and C1-inhibitor expression Figure 1 are neuroprotective too, improving blood flow and neurological recovery after transient ischemia, and reducing the intracerebral edema following hemorrhage Vasthare et al.
schollitllodemo.ml C1q, C3b, and C3d have been found close to the ischemic penumbra Lindsberg et al. All these data show the putative role of complement activation in tissue recovering after AIS, thus offering new perspectives on the role of complement during the postictal plastic reorganization.
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Thrombin effects depend on its concentration: the increase produces an adaptive-maladaptive gradient Maggio et al.
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