Following injury, the peripheral nervous system (PNS) possesses a pronounced regenerative capacity, while regeneration is insufficient and remains abortive in central nervous system (CNS) disease. The relatively enhanced regeneration of the PNS is in part attributed to the plasticity of Schwann cells, the major class of PNS glia . Schwann cells undergo a remarkable transformation in response to injury, characterized by a transient period of proliferation and extensive changes in gene expression . Although many of these molecular changes result in a cellular status reminiscent of immature Schwann cells , recent work implies that the post-injury stage of Schwann cells represents an unique phenotype, promoting repair and lacking several features found in other differentiation stages of the Schwann cell lineage.Although Schwann cells are not a physiological component of the CNS, recent evidence indicates that they crucially contribute to the cellular response following CNS injury under certain circumstances. Schwann cell participation has been largely described in experimental animal models for spinal cord trauma and toxic demyelination caused by injection of substances such as kainate, ethidium bromide, 6-aminonicotinamide, and lysolecithin . Interestingly, Schwann cell-mediated remyelination is a well-known phenomenon in the spinal cord of patients suffering from multiple sclerosis (MS), the major human demyelinating condition . Although data upon the exact role of these cells in terms of functional effects are lacking so far, it is suggested that Schwann cells might contribute to significant CNS regeneration. Their origin, however, in naturally occurring diseases remains unclear so far. In particular, it remains to be determined whether the presence of an immature or post-injury Schwann cell phenotype promotes CNS regeneration under natural circumstances. Strikingly, the origin of Schwann cells within the CNS is controversially discussed. On the one hand, experimental and naturally occurring spinal cord injury studies demonstrated that immature/dedifferentiated Schwann cells expressing the prototype marker p75 neurotrophin receptor (p75NTR) migrate into the lesioned site from PNS sources such as spinal nerve roots . On the other hand, lineage-tracing studies have clearly shown that CNS-resident precursors are the major source of Schwann cell-mediated remyelination within toxic CNS demyelination lesions of mice, while only very few remyelinating Schwann cells invade the CNS from PNS sources . Additionally, in vitro studies suggest that p75NTR-expressing Schwann cells derived from the CNS share several properties with oligodendrocyte precursor cells (OPCs), including similar voltage-gated potassium channels (Kv) activation and antigenic expression, substantiating that these cells might represent centrally generated, pre-myelinating Schwann cells However, the relationship between canine CNS Schwann cells and OPCs in vivo remained unresolved. Irrespective of their exact origin, it remains to be resolved, which mechanisms function as triggering factors for the occurrence of Schwann cells in the CNS.To address the former aspects, we aimed to investigate naturally occurring lympho-histiocytic encephalitis and granulomatous meningoencephalitis (GME), two CNS idiopathic inflammatory entities of dogs, grouped as non-suppurative meningoencephalitis of unknown origin. The suitability of this model is based on several observations.
First, it belongs to a group of idiopathic diseases with suspected autoimmune and/or multifactorial etiopathogenesis with no infectious etiology proved to date], thus resembling the etiopathogenesis of multiple sclerosis (MS) or other immune-mediated CNS diseases in some aspects. Secondly, similar to MS, etiologically undertermined lympho-histiocytic encephalitis and GME are characterized by a multifocal distribution pattern, involving primarily the white matter and perivascular infiltration consisting mainly of macrophages and T cells. Thirdly, mRNA expression and protein levels of IL-17 and IFN-γ detected in lesions of dogs suffering from GME are comparable to those described in MS and murine experimental autoimmune encephalitis (EAE) . In addition, mRNA expression of chemokine receptors, such as chemokine (C-X-C motif) receptor 3 (CXCR3), C-C chemokine receptor type 2 (CCR2), and C-C chemokine receptor type 4 (CCR4), also implicated in MS and EAE pathogenesis, are described to play a role in the formation of GME lesions. Finally, many conditions in the species dog share striking similarities with their human counterparts thus representing suitable translational models for studying human aging , spinal cord injury and MS, as described in the canine distemper virus (CDV)-induced demyelination model. Moreover, canine glial cells recently gained attention in cell-based therapies , which is in part due to their primate-like properties regarding in vitro proliferation and marker expression . The major strength of the model is based on the spontaneous occurrence of the lesions. Thus, the species dog might help to overcome the gap between highly homogenous and standardized lesions in experimental rodent models and clinically relevant conditions in humans. In this study, we analyzed the spatial distribution and the identity of p75NTR-expressing cells and mature myelinating Schwann cells within the brains of dogs with non-suppurative meningoencephalitis of unknown origin, and compared the observed expression profiles with those of a case of peripheral nerve injury, and with healthy sciatic nerves and canine brains. This is the first study, which characterizes in detail the Schwann cell phenotype in the injured brain, therewith providing novel insights into the involvement of Schwann cells under naturally occurring pathophysiological circumstances in the CNS.Large hypertrophic astrocytes were present in all lesioned areas. GFAP immunoreactivity revealed a marked astrogliosis in p75NTR-/PRX–, p75NTR+/PRX–, and p75NTR+/PRX+ lesioned areas localized in the cerebral and cerebellar white matter as compared with controls. However, there was no difference in its expression between the three lesion types. In the brain stem , GFAP-expression did neither significantly vary between the investigated lesion types nor between lesions and controls . In the cerebral and cerebellar white matter and in the brain stem, CD3-positive T lymphocyte numbers were significantly lower in p75NTR+/PRX+ and p75NTR+/PRX– lesions when compared to p75NTR-/PRX– areas . The number of BS-1-positive microglia/macrophages did not show any significant differences between the lesion groups concerning the anatomic localization . CD3-positive T lymphocytes and BS-1-positive microglia/macrophages were not observed in any anatomical localization of control dogs.
