Abstract: 110
Type: Oral
Protection of the CNS from leakage of plasma proteins by the blood-brain barrier (BBB) is lifted in a wide range of neuroimmune and neurodegenerative diseases. However, whether blood proteins contribute to neuroinflammation and neuronal damage remains poorly understood. Our laboratory has discovered unanticipated functions for the blood coagulation factor fibrinogen as a key upstream activator of CNS innate immunity inducing robust activation of microglia and recruitment of peripheral macrophages into the CNS1. Fibrinogen is abundantly deposited in the brain in multiple sclerosis (MS) lesions1. We showed that fibrinogen is a potent pro-inflammatory mediator in the nervous system by activating the CD11b/CD18 integrin receptor (also known as Mac-1 and complement receptor 3) in microglial cells2. Fibrinogen stimulates a unique transcriptional signature in microglia inducing chemokine release and the recruitment of peripheral immune cells into the CNS3. Using in vivo two-photon imaging, we showed in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS that microglia perform constant surveillance of blood vessel walls and specifically cluster around blood vessels with fibrin deposition4. Genetic disruption of the fibrinogen/CD11b interaction suppresses microglial cluster formation, neurologic symptoms, inflammation, demyelination, and axonal damage in EAE2,4. Furthermore, by developing a molecular probe to detect thrombin activation in the CNS, we demonstrated that activation of the coagulation cascade preceded onset of neurological signs, increased at disease peak, and correlated with fibrin deposition, microglial activation, demyelination, axonal damage, and clinical severity in EAE5. These studies identified the blood coagulation factor fibrinogen as a novel molecular link between BBB disruption, activation of CNS innate immunity, and neurodegeneration. Our drug discovery approach based on a novel fibrin-directed immunotherapy that selectively targets the proinflammatory functions of fibrin without affecting its beneficial effects in hemostasis will be discussed.
1. Davalos & Akassoglou, Semin Immunopathol. 2012. 34:43-62
2. Adams et al., J Exp Med. 2007. 204:571-82
3. Ryu et al., Nat Commun 2015, 6:8164.
4. Davalos et al., Nat Commun. 2012; 3:1227
5. Davalos et al., Ann Neurol 2014, 75:303-308
Disclosure: Funding: NIH/NINDS R01 NS052189, R01 NS051470, R21 NS082976; National Multiple Sclerosis Society RG 4985A3, Conrad N. Hilton Foundation, Lundbeck
COI: Dr. Akassoglou is a named inventor on two patents regarding fibrin and has received research grants and served as a consultant for Lundbeck.
Abstract: 110
Type: Oral
Protection of the CNS from leakage of plasma proteins by the blood-brain barrier (BBB) is lifted in a wide range of neuroimmune and neurodegenerative diseases. However, whether blood proteins contribute to neuroinflammation and neuronal damage remains poorly understood. Our laboratory has discovered unanticipated functions for the blood coagulation factor fibrinogen as a key upstream activator of CNS innate immunity inducing robust activation of microglia and recruitment of peripheral macrophages into the CNS1. Fibrinogen is abundantly deposited in the brain in multiple sclerosis (MS) lesions1. We showed that fibrinogen is a potent pro-inflammatory mediator in the nervous system by activating the CD11b/CD18 integrin receptor (also known as Mac-1 and complement receptor 3) in microglial cells2. Fibrinogen stimulates a unique transcriptional signature in microglia inducing chemokine release and the recruitment of peripheral immune cells into the CNS3. Using in vivo two-photon imaging, we showed in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS that microglia perform constant surveillance of blood vessel walls and specifically cluster around blood vessels with fibrin deposition4. Genetic disruption of the fibrinogen/CD11b interaction suppresses microglial cluster formation, neurologic symptoms, inflammation, demyelination, and axonal damage in EAE2,4. Furthermore, by developing a molecular probe to detect thrombin activation in the CNS, we demonstrated that activation of the coagulation cascade preceded onset of neurological signs, increased at disease peak, and correlated with fibrin deposition, microglial activation, demyelination, axonal damage, and clinical severity in EAE5. These studies identified the blood coagulation factor fibrinogen as a novel molecular link between BBB disruption, activation of CNS innate immunity, and neurodegeneration. Our drug discovery approach based on a novel fibrin-directed immunotherapy that selectively targets the proinflammatory functions of fibrin without affecting its beneficial effects in hemostasis will be discussed.
1. Davalos & Akassoglou, Semin Immunopathol. 2012. 34:43-62
2. Adams et al., J Exp Med. 2007. 204:571-82
3. Ryu et al., Nat Commun 2015, 6:8164.
4. Davalos et al., Nat Commun. 2012; 3:1227
5. Davalos et al., Ann Neurol 2014, 75:303-308
Disclosure: Funding: NIH/NINDS R01 NS052189, R01 NS051470, R21 NS082976; National Multiple Sclerosis Society RG 4985A3, Conrad N. Hilton Foundation, Lundbeck
COI: Dr. Akassoglou is a named inventor on two patents regarding fibrin and has received research grants and served as a consultant for Lundbeck.