Abstract
Myelin-associated inhibition of axonal regrowth after injury is considered one important factor that contributes to regeneration failure in the adult central nervous system (CNS). Blocking strategies targeting this pathway have been successfully applied in several nerve injury models, including experimental autoimmune encephalomyelitis (EAE), suggesting myelin-associated inhibitors (MAIs) and functionally related molecules as targets to enhance regeneration in multiple sclerosis. NgR1 and NgR2 were identified as interaction partners for the myelin proteins Nogo-A, MAG and OMgp and are probably mediating their growth-inhibitory effects on axons, although the in vivo relevance of this pathway is currently under debate. Recently, alternative functions of MAIs and NgRs in the regulation of immune cell migration and T cell differentiation have been described. Whether and to what extent NgR1 and NgR2 are contributing to Nogo and MAG-related inhibition of neuroregeneration or immunomodulation during EAE is currently unknown. Here we show that genetic deletion of both receptors does not promote functional recovery during EAE and that NgR1 and NgR2-mediated signals play a minor role in the development of CNS inflammation. Induction of EAE in Ngr1/2-double mutant mice resulted in indifferent disease course and tissue damage when compared to WT controls. Further, the development of encephalitogenic CD4+ Th1 and Th17 responses was unchanged. However, we observed a slightly increased leukocyte infiltration into the CNS in the absence of NgR1 and NgR2, indicating that NgRs might be involved in the regulation of immune cell migration in the CNS. Our study demonstrates the urgent need for a more detailed knowledge on the multifunctional roles of ligands and receptors involved in CNS regeneration failure.
Highlights
The non-regenerative nature of the adult mammalian central nervous system (CNS) poses a major challenge to successful repair of nerve damage occurring by either traumatic injury or during inflammatory CNS diseases such as Multiple Sclerosis (MS)
Strategies aiming at the improvement of axonal regeneration and repair are currently in clinical development and are clearly desirable for patients suffering from traumatic injury as well as from diseases like MS, which is associated with axonal transections, neuronal loss and chronic disability accumulation
We provide evidence that two proteins involved in the negative regulation of axonal regrowth and plasticity by mammalian CNS (MAIs), NgR1 and NgR2, are dispensable with respect to maintaining myelin-associated inhibition of axonal regrowth in the development and progression of autoimmune inflammatory neurodegeneration in EAE, an established animal model of the human disease MS
Summary
The non-regenerative nature of the adult mammalian central nervous system (CNS) poses a major challenge to successful repair of nerve damage occurring by either traumatic injury or during inflammatory CNS diseases such as Multiple Sclerosis (MS). Most likely driven by a deregulated myelin-specific autoreactive CD4+ T cell response, this disease leads to chronic inflammation, demyelination, and neuronal and axonal degeneration [1,2]. The latter two outcomes are considered to be the major determinants of clinical disability in patients [3,4,5]. Nogo receptors were identified as interaction partners for three myelin proteins associated with the inhibition of axonal regeneration in the adult mammalian CNS (MAIs) – Nogo, myelinassociated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp) [9,10,11]. Many components of this regulatory system have been identified by extensive and detailed studies, their relative contribution to CNS regeneration failure in vivo is still poorly understood
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