Contributions
Abstract: P407
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Experimental models
The general dogma suggests that the formation of new lesions in Multiple sclerosis begins with an immune dysregulation, with the consequence that the immune system targets the brain compartment, resulting in active demyelinating foci. Other studies, however, have proposed that brain-intrinsic degenerative cascades are the initial factors driving Multiple sclerosis lesion formation, including oligodendrocyte death, focal microglia activation, or axonal damage. We recently provided experimental evidence for the latter hypothesis recruitment (see Scheld et al and Kipp; J Neurosci. 2016 Jan 27;36(4):1410-5). There, we were clearly able to show that neurodegeneration is a potent trigger for peripheral immune cell recruitment into the forebrain.
In this work we demonstrate that the amelioration of oligodendrocyte and neuronal degeneration results in lower, secondary immune-cell infiltration in this novel Multiple sclerosis animal model. We identified by genome-wide array analyses Ddit3/Chop as an early regulator of oligodendrocyte apoptosis. Ddit3 is exclusively expressed in oligodendrocytes during initial cuprizone-induced cytodegeneration, and early oligodendrocyte apoptosis is reduced in Ddit3-deficient mice. This initial protection is paralleled at later stages by less severe demyelination, microgliosis and axonal damage. Furthermore, Ddit3-deficient mice show reduced forebrain peripheral immune cell recruitment after subsequent MOG-immunization.
This study clearly illustrates the importance of brain-intrinsic degenerative cascades for immune-cell recruitment and thus Multiple sclerosis lesion formation. Dampening of cytodegenerative signaling cascades results in less severe immune cell recruitment. A better understanding of involved factors would allow for the first time an effective hand-in-hand intervention against both, degenerative and inflammatory aspects of the disease.
Disclosure: Malin Gottschling: nothing to disclose
Miriam Scheld: nothing to disclose
Sven-Olaf Rohr: nothing to disclose
Tim Clarner: nothing to disclose
Markus Kipp: nothing to disclose
This study was supported by the Doktor Robert-Pfleger Fundation.
Abstract: P407
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Experimental models
The general dogma suggests that the formation of new lesions in Multiple sclerosis begins with an immune dysregulation, with the consequence that the immune system targets the brain compartment, resulting in active demyelinating foci. Other studies, however, have proposed that brain-intrinsic degenerative cascades are the initial factors driving Multiple sclerosis lesion formation, including oligodendrocyte death, focal microglia activation, or axonal damage. We recently provided experimental evidence for the latter hypothesis recruitment (see Scheld et al and Kipp; J Neurosci. 2016 Jan 27;36(4):1410-5). There, we were clearly able to show that neurodegeneration is a potent trigger for peripheral immune cell recruitment into the forebrain.
In this work we demonstrate that the amelioration of oligodendrocyte and neuronal degeneration results in lower, secondary immune-cell infiltration in this novel Multiple sclerosis animal model. We identified by genome-wide array analyses Ddit3/Chop as an early regulator of oligodendrocyte apoptosis. Ddit3 is exclusively expressed in oligodendrocytes during initial cuprizone-induced cytodegeneration, and early oligodendrocyte apoptosis is reduced in Ddit3-deficient mice. This initial protection is paralleled at later stages by less severe demyelination, microgliosis and axonal damage. Furthermore, Ddit3-deficient mice show reduced forebrain peripheral immune cell recruitment after subsequent MOG-immunization.
This study clearly illustrates the importance of brain-intrinsic degenerative cascades for immune-cell recruitment and thus Multiple sclerosis lesion formation. Dampening of cytodegenerative signaling cascades results in less severe immune cell recruitment. A better understanding of involved factors would allow for the first time an effective hand-in-hand intervention against both, degenerative and inflammatory aspects of the disease.
Disclosure: Malin Gottschling: nothing to disclose
Miriam Scheld: nothing to disclose
Sven-Olaf Rohr: nothing to disclose
Tim Clarner: nothing to disclose
Markus Kipp: nothing to disclose
This study was supported by the Doktor Robert-Pfleger Fundation.