Tesis doctoral de Miriam Hernangomez Herrero
Summary inflammatory activation of microglia is a pathological hallmark of multiple sclerosis (ms). Cd200 is a membrane glycoprotein belonging to the igsf highly expressed on neurons that delivers a signal involved in immune suppression via its recep tor cd200r confined mainly to myeloid cells like macrophages and microglia. through cd200-cd200r interaction, the activity of macrophages and microglia can be down-regulated. Evidence shows that the endocannabinoid anandamide (aea) protects neurons d uring cns inflammation by targeting microglia. Here, we investigate the effects of aea on cd200-cd200r1 interactions in neuroinflammatory conditions and in particular in ms. In theiler¿s murine encephalomyelitis virus-induced demyelinating disease (t mev-idd) we found decreased expression levels of cd200 and cd200r in chronic phases of the disease. The activation of the endocannabinoid system by enhancing aea tone by i) administering an inhibitor of aea uptake, ii) administering an inhibitor of a ea hydrolysis, or iii) application of aea mini-osmotic pumps led to upregulation of cd200 and cd200r in the spinal cord of tmev-infected mice. These findings were associated with decreased il-1? And increased il-10 expression, and as expected fewer a ctivated microglia were present in the spinal cord. Importantly, increased aea tone improved tmev-idd symptomatology. Treatment of neuronmicroglia co-cultures with a soluble form of cd200, cd200fc, protected neurons from microglia-induced neurotoxici ty in vitro. The neuroprotective effect of cd200fc was completely prevented when microglial cells were obtained from cd200r1-/- mice. additionally, microglia-mediated neuronal damage was significantly diminished by aea, an effect that was prevented b y using microglia from cd200r1-/- mice. We have preliminary evidence that the endocannabinoid 2-arachidonoylglycerol decreased neuronal damage in microglia-neuron co-cultures through cd200-cd200r1 interaction. The engagement of cd200r1 by the fusion protein cd200fc decreased the production of the proinflammatory cytokines il-1? And il-6, but increased il-10 in activated microglia. cd200r1 expression was down-regulated in microglia by lps/ifn-? Stimuli. In vitro treatment of microglial cells with aea up-regulated the expression of cd200r1 by a cb2-dependent mechanism. Cb2 receptor signaling on microglial cells includes the synthesis of the anti-inflammatory cytokine il-10. Treatment of neuronal cultures with aea did not modify the level of e
Datos académicos de la tesis doctoral «Respuesta inmune innata en el snc: cd200-cd200r en un modelo viral de esclerosis múltiple.«
- Título de la tesis: Respuesta inmune innata en el snc: cd200-cd200r en un modelo viral de esclerosis múltiple.
- Autor: Miriam Hernangomez Herrero
- Universidad: Complutense de Madrid
- Fecha de lectura de la tesis: 25/10/2010
Dirección y tribunal
- Director de la tesis
- Carmen Guaza Rodriguez
- Tribunal
- Presidente del tribunal: María monica De la fuente del rey
- Francisco Molina holgado (vocal)
- Luis Miguel García segura (vocal)
- ángel Luis Arévalo martín (vocal)