Increased p75 neurotrophin receptor expression in the canine distemper virus model of multiple sclerosis identifies aldynoglial schwann cells that emerge in response to axonal damage

Abstract

Gliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide regeneration-promoting cells recruitable for therapeutic purposes. There is accumulating evidence that aldynoglial cells with Schwann cell-like growth-promoting properties emerge in the lesioned CNS. However, the characterization of these cells and the signals triggering their in situ generation have remained enigmatic. In the present study, we used the p75 neurotrophin receptor (p75(NTR) ) as a marker for Schwann cells to study gliogenesis in the well-defined canine distemper virus (CDV)-induced demyelination model. White matter lesions of CDV-infected dogs contained bi- to multipolar, p75(NTR) -expressing cells that neither expressed MBP, GFAP, BS-1, or P0 identifying oligodendroglia, astrocytes, microglia, and myelinating Schwann cells nor CDV antigen. Interestingly, p75(NTR) -expression became apparent prior to the onset of demyelination in parallel to the expression of β-amyloid precursor protein (β-APP), nonphosphorylated neurofilament (n-NF), BS-1, and CD3, and peaked in subacute lesions with inflammation. To study the role of infiltrating immune cells during differentiation of Schwann cell-like glia, organotypic slice cultures from the normal olfactory bulb were established. Despite the absence of infiltrating lymphocytes and macrophages, a massive appearance of p75(NTR) -positive Schwann-like cells and BS-1-positive microglia was noticed at 10 days in vitro. It is concluded that axonal damage as an early signal triggers the differentiation of tissue-resident precursor cells into p75(NTR) -expressing aldynoglial Schwann cells that retain an immature pre-myelin state. Further studies have to address the role of microglia during this process and the regenerative potential of aldynoglial cells in CDV infection and other demyelinating diseases.

New Aspects of the Pathogenesis of Canine Distemper Leukoencephalitis

“…The demonstration of a lacking co-localization with markers specific for astrocytes, microglia, and mature oligodendrocytes substantiates that the detected p75 NTR -immunoreactive bi- to multipolar cells in CDV-DL lesions represent a distinct and unique glial population, similar to p75 NTR expressing macroglia in vitro [143]. Despite observations in vitro , which demonstrate high susceptibility of p75 NTR positive macroglia for CDV infection, there is no evidence that p75 NTR -positive cells are infected by CDV in situ as demonstrated by lacking immunohistochemical co-localization of CDV antigen and p75 NTR [41,143]. The highest number of p75 NTR -positive glia is seen in dogs with subacute lesions with remarkable inflammation.…”

“…Subsequently, CDV-DL follows a certain time course, which strikingly correlates with neuropathological alterations. A well-described histological classification scheme has been used by several authors in order to categorize white matter lesions (Figure 1) [39,40,41]. In this respect, acute, subacute, and chronic lesions are distinguished (Figure 1).…”

“…However, a glial cell type with Schwann cell-like properties in adult canine brain was identified in vitro as early as 2008, where these cells displayed a spindle-shaped morphology three weeks after seeding [143]. Strikingly, the role of p75 NTR expression has recently been described in dogs suffering from naturally occurring CDV-DL, highlighting this molecule as a potential candidate for endogenous regenerative events following CDV infection [41]. While in non-infected control dogs p75 NTR expression is limited to blood vessels and to the periphery of leptomeningeal vessels, p75 NTR is additionally expressed on bipolar, spindle-shaped cells, morphologically reminiscent of Schwann-like cells in dogs with CDV-DL [41].…”

“…Strikingly, the role of p75 NTR expression has recently been described in dogs suffering from naturally occurring CDV-DL, highlighting this molecule as a potential candidate for endogenous regenerative events following CDV infection [41]. While in non-infected control dogs p75 NTR expression is limited to blood vessels and to the periphery of leptomeningeal vessels, p75 NTR is additionally expressed on bipolar, spindle-shaped cells, morphologically reminiscent of Schwann-like cells in dogs with CDV-DL [41]. In addition and not observed in control dogs, a comparatively low expression is noted on stellate-shaped cells, suggestive of microglia.…”

“…This interesting finding implicates that factors other than demyelination itself might function as triggering events that contribute to the differentiation of such cells. Interestingly, p75 NTR expression on Schwann like glia strictly parallels axonal pathology, as demonstrated by immunoreactivity of axons for n-NF and axonal expression of β-APP [41]. Thus, early axonal damage might represent a pivotal initial pathogenetic mechanism that triggers the occurrence of these cells (Figure 2) [41].…”