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Fibrin(ogen): friend and foe
lifestyle changes, may help to prolong survival in cancer patients. Likewise, other approaches targeting fibrinogen- dependent interactions (e.g., inhibitors of fibrinogen-αMβ2 interactions) may also prove useful in cancer treatment and/or prevention.73
Neurological disorders
The biological complexity of several neurological dis- eases involving the CNS, such as Alzheimer disease and multiple sclerosis, is not yet fully understood. However, the need to study CNS cells within their environmental context is clear.
The brain vasculature consists of dynamic metabolic structures that work as a continuum from artery to arte- riole to capillary to venule to vein.83,84 The blood-brain barrier (BBB) is essential to separate blood from extracel- lular fluid in the CNS. The BBB is formed by endothelial cells that maintain critical interactions with other cells, together with a basement membrane that affords an anchor for many signaling processes at the vasculature.84 By providing a dynamic physical and metabolic barrier between the CNS and systemic circulation, the BBB ensures constant protection of the neural microenviron- ment from the influx of potentially harmful substances including plasma proteins, immune cells, pathogens and drugs, while maintaining the efflux of toxins and waste products.83,84 Disruption of the BBB is an early event that occurs in many neurological disorders, such as Alzheimer disease, in which, along with microglial activation and neuronal cell death, the neuropathological hallmarks include extracellular deposition of amyloid-β (Aβ) in senile plaques and blood vessel walls, and the intracellular accu- mulation of neurofibrillary tangles containing phosphory- lated tau proteins.85 Brain micro-hemorrhages are fre- quently observed in patients with Alzheimer disease, and BBB disruption correlates with disease progression.86 In animal models of Alzheimer disease, BBB leakage pre- cedes other neuropathological alterations in the brain,87 suggesting that damage to the barrier is implicated in the initiation and progression of the disease.85 BBB disruption is also one of the earliest representative events in the pathology of multiple sclerosis.88 Indeed, BBB disturbance is linked to the inflammation and white matter injury that define this neuroinflammatory disorder.83,85 Fibrinogen may extravasate into the CNS upon such events. Once in the brain, fibrin(ogen) can induce signaling networks via binding sites for multiple receptors and proteins, acting as a mediator of neurodegeneration and an activator of innate immunity.85
Fibrin deposits are found in early multiple sclerosis lesions and areas of demyelination in close association with inflammation and damaged axons.89 In Alzheimer disease, fibrin deposits accumulate within CNS blood ves- sels in conjunction with cerebral amyloid angiopathy.90 In the perivascular brain parenchyma, fibrin co-localizes with Aβ plaques,91 macrophages,92 areas of pericyte loss93 and dystrophic neurites.94
Fibrin formation exposes the cryptic epitope γ377–395, which binds with high affinity to the αMβ2 integrin on microglia and infiltrating macrophages, activating multiple signal transduction pathways to promote inflammatory responses. This is associated with antigen presentation, release of reactive oxygen species95 and secretion of the
leukocyte-recruiting chemokines CCL2, and CXCL10.96 In multiple sclerosis this may lead to T-cell recruitment and local differentiation of myelin antigen-specific T helper 1 cells to promote autoimmunity and demyelination.96 In animal models of Alzheimer disease, fibrin(ogen) was shown to accumulate in areas of dendritic spine elimina- tion, even independently and distal to Aβ peptides that aggregate to form neurotoxic and stable oligomers, with ensuing cognitive impairment.97 The fibrinogen-mediated elimination depends on microglial αMβ2 receptor activation and generation of reactive oxygen species. However, the fibrin-Aβ interaction has an additive effect on poor out- come. Aβ can activate contact pathway coagulation to drive fibrin formation,98 protect fibrin from degradation99 and allow a constant inflammatory signal.
Fibrin(ogen) contributes to neurological disease by inhibiting remyelination after vascular damage.85 Fibrinogen can activate bone morphogenetic protein (BMP) receptor activin A receptor type I and downstream BMP-specific SMAD proteins in oligodendrocyte progeni- tor cells, independently of BMP ligands.100 This prevents oligodendrocyte progenitor cells from differentiating into myelinating oligodendrocytes and promotes an astrocyte- like cell fate. Fibrin-M1-like activation of microglia101 and macrophages96 can also be toxic to oligodendrocyte pro- genitor cells and further impair remyelination.85 Another possible mechanism is through fibrin-induced phosphory- lation of extracellular signal-regulated kinases and produc- tion of nerve growth factor receptor in Schwann cells, maintaining them in a proliferating, non-myelinating state.102
Neurite outgrowth inhibition103 and glial scar forma- tion104 may also be triggered by fibrinogen, leading to cere- brovascular pathologies. Fibrinogen inhibits neurite out- growth by binding the αVβ3 integrin and trans-activating epidermal growth factor receptor in neurons.103 Inhibition of axonal regeneration occurs indirectly by prompting astrocytosis and stimulating the production of inhibitory proteoglycans that form the glial scar. Fibrinogen can carry a latent transforming growth factor-β that is activated when it encounters primary astrocytes, stimulating the production of neurocan, a strong inhibitor of neurite out- growth.104
Consistent with these observations, reducing fibrinogen levels with ancrod,105 manipulating the conversion of fib- rinogen into insoluble fibrin with hirudin101 and interfering with fibrinolysis by tissue plasminogen activator106 all attenuated injuries and promoted regeneration and func- tional recovery. Similar results were also obtained after treatment with γ377–395 peptide107 or a monoclonal anti- body against the same epitope,108 revealing an essential role for fibrin in peripheral nerve damage and repair.
In summary, fibrin(ogen) can induce degenerative changes in the CNS through different mechanisms that initiate or potentiate neurodegenerative processes after vascular disruption (Figure 3A). While many studies have found that fibrin(ogen) promotes neuroinflammation through binding to the αMβ2 integrin on macrophages and microglia, pericyte-deficient mice lack a significant neu- roinflammatory response until late in the disease. These mice suffer from early BBB breakdown and accumulation of white matter fibrin(ogen) that is associated with dimin- ished blood flow and hypoxia. However, following white- matter injury, no changes were detected in astrocyte, microglia or macrophage responses or pro- and anti-
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