Brain fibrinogen deposition plays a key role in MS pathophysiology - Yes

Abstract

Blood-brain barrier (BBB) disruption, perivascular inflammation, demyelination, and axonal damage are key histopathological hallmarks of multiple sclerosis (MS)^1–3. The vast majority of MS lesions develop around disrupted blood vessels. This is often attributed to active inflammation and the infiltration of immune cells into the central nervous system (CNS). Indeed, evidence of BBB disruption by gadolinium enhancement on magnetic resonance imaging (MRI) constitutes the most reliable indication of active inflammatory MS lesions. However, increasing evidence highlights a more central role for the leakage of blood factors into the CNS -an inevitable consequence of BBB disruption- whose entry precedes and promotes new lesion formation. Fibrinogen is a soluble blood protein known for its role in coagulation, through its rapid conversion to fibrin, the foundation of blood clots^{1, 3}. Analyses in human MS tissue and in several animal models identified fibrinogen in the CNS prior to leukocyte infiltration, and the onset of demyelination, or clinical symptoms. Moreover, extensive preclinical studies demonstrated that fibrinogen is unique among other blood proteins or coagulation factors that may also enter the CNS, as it promotes inflammatory processes within perivascular lesions, and thereby contributes to neuronal damage, and inhibits tissue repair processes.

Fibrinogen enters the CNS early and persists throughout MS lesion progression

Among blood and coagulation factors that can seep into the MS brain, fibrinogen is the only one that does not simply leak and diffuse in the parenchyma, but instead gets rapidly converted to fibrin, an insoluble extracellular matrix component that persists in the tissue around leaky blood vessels¹. But fibrinogen is more than a reliable indicator of BBB disruption, as it strongly correlates with inflammatory activity in both human MS and its animal models. Several postmortem studies have found extensive fibrinogen deposits around blood vessels not only in active, chronic active, and chronic inactive MS lesions, but importantly also in pre-active ones^{2, 3}. Pre-active and active white matter (WM) lesions show increasing perivascular fibrinogen distribution, which becomes more diffuse as lesions evolve to chronic active or inactive³. This is probably a consequence of fibrinolysis, which initiates fibrin degradation as soon as fibrin forms^{1, 3}. Similarly, perivascular fibrinogen is sparse in re-myelinated lesions and of course absent in normal appearing WM^{2, 3}. Deep grey matter (GM) structures also have perivascular fibrinogen deposition associated with inflammation, but to a lesser extent than in WM⁴. Finally, fibrinogen deposition was also detected in the cortex of patients with progressive MS⁵. Similar to analyses in human material, studies in experimental autoimmune encephalomyelitis, (EAE, an established animal model for MS), showed fibrinogen deposition in the CNS before the onset of demyelination, T cell infiltration, axonal damage, or clinical signs of disease in mice and marmosets^{3, 6}.

Fibrinogen deposition correlates with BBB disruption and with MS histopathology

Numerous studies have shown increased levels of fibrinogen deposition within demyelinating lesions, swarming with activated innate and adaptive immune cells¹. In addition to inflammation fibrinogen also correlates with axonal pathology and neuronal loss. It co-localizes extensively with axons in chronic active and inactive lesions³ and neuronal loss in cortical GM in progressive MS⁵, and in active WM lesions with demyelination (pattern III), where it was also found inside astrocytes and neurons^{2, 5}. Interestingly, in pre-active lesions, fibrinogen deposits appear attached to axonal nodes and co-localize with microglia showing early signs of activation, prior to peripheral immune cell infiltration or any detectable tissue damage^{2, 3}. The evidence of dysregulation in both coagulation and fibrinolytic cascades can explain the presence of coagulation factors in MS lesions, and the persistence of fibrinogen over their pathological evolution from pre-active to chronic^{5, 7}. Although spatial correlation or increased amounts within MS lesions of factors normally absent from the CNS might suggest possible roles for them, co-localization alone hardly qualifies as proof of mechanistic involvement with MS pathology. Fibrinogen is unique among blood and coagulation components in its ability to promote innate immune activation and thereby drive local inflammation that can directly damage myelin and neurons.

Fibrinogen promotes new lesion formation and inhibits tissue repair

The conversion of fibrinogen to fibrin not only guarantees its persistent CNS presence, but also exposes an epitope on fibrin that is cryptic on fibrinogen^{1, 3}. This epitope specifically binds to CD11B/CD18 (or α_Mβ₂) integrin receptor, which is absent from all CNS cells except microglia and CNS–resident or infiltrating macrophages¹. Extensive preclinical work showed that this ligand–receptor interaction induces microglial clustering around leaky blood vessels, promotes chemokine secretion and recruitment of peripheral macrophages and myelin specific Th1 cells into the CNS, and is essential for demyelination and axonal damage^{6, 8}. Mechanistically, fibrinogen binding to microglia/macrophages promotes their inflammatory activation resulting in morphological changes, increased phagocytosis, upregulation of genes responsible for oxidative stress, and release of proinflammatory and cytotoxic mediators that damage neurons^{6, 8–10}. Furthermore, fibrinogen impairs tissue repair processes by inhibiting oligodendrocyte precursor cell differentiation and inducing NADPH/ROS mediated neurodegeneration^{3, 10}.

Selective inhibition of fibrinogen–induced inflammation protects from MS-like disease

Upon BBB disruption, several blood components and coagulation factors gain access to the CNS. The immediate initiation of coagulation results in the conversion of fibrinogen –a rather benign soluble molecule in the bloodstream to fibrin –a potent activator of autoimmune responses in the CNS. Experiments using mice with mutations only in the fibrinogen gene showed that it is unique among blood proteins in inducing immune activation and neuroinflammatory disease^{6, 8, 9}. Anticoagulant treatments have shown protection from disease in several animal models of MS^{1, 3, 6, 9}. Although inhibiting coagulation in general could protect from neuroinflammation, losing the ability to stop accidental bleeding would pose substantial risks. Crucially, recent efforts to specifically target the inflammatory function of fibrinogen without interfering with its role in coagulation showed robust protection from disease in prophylactic and therapeutic preclinical models of MS^{6, 9, 10}. Fibrinogen is an essential component of coagulation and a life–saving blood factor; deciphering the specific epitope– receptor interaction through which it exerts sustained and thus harmful inflammatory effects presents a unique opportunity for therapeutic intervention. With elegant molecular targeting in a novel therapeutic direction, this target deserves a fair chance to develop into a novel therapeutic for patients with MS.