Neuroinflammation in white matter tracts of Cnp1 mutant mice amplified by a minor brain injury

Abstract

Oligodendrocytes make myelin for rapid impulse propagation and contribute to the long-term survival of myelinated axons. The mechanisms by which oligodendroglial dysfunction(s) contribute to slowly progressive neurodegeneration are not well understood. Here, we demonstrate in Cnp1 mutant mice that secondary axonal degeneration in the subcortical white matter is associated with an age-dependent activation of both, innate and adaptive immune responses, including an expansion of infiltrating CD8+ T cells. While the detrimental role of lymphocytes in inherited myelin diseases is known, the role of activated microglia for the hypothetical cycle of inflammation/degeneration is unclear. We used a mild standardized cryolesion of the right parietal cortex to activate microglia at the vulnerable age of mouse puberty (postnatal day (P) 28). When applied to Cnp1 mutant mice, analyzed more than 3 months later, minor brain injury had acted as a "second hit" and significantly enhanced astrogliosis, microgliosis and axon degeneration, but not T cell infiltration. Interestingly, exacerbated neuropathological changes were also reflected by specific deterioration of working memory on top of an essentially normal basic behavior. We propose a model in which oligodendroglial dysfunctions can trigger a vicious cycle of neurodegeneration and low-grade inflammation that is amplified by nonspecific activators of the innate immune system. This interaction of genetic and environmental factors may be relevant for neuropsychiatric diseases associated with secondary neuroinflammation.

Microglia ablation alleviates myelin-associated catatonic signs in mice

“…The CSF1R inhibitor also proved effective for treatment of existing catatonia in older Cnp -/-mutants, in which it caused a reduction (but not prevention) of axonal degeneration. This is in line with CNP deficiency as a "driver" of neurodegeneration following traumatic brain injury (42). However, the complete prevention of catatonic signs in the young Cnp-null mutants strongly suggests that catatonia is not caused by axonal degeneration but is primarily a "microglial disease" induced by mild myelin perturbations.…”

Pathoetiology of multiple sclerosis: are we barking up the wrong tree?

“…Histopathology of this knockout mouse reveals pronounced infiltration in the CNS, mainly by CD8+ T cells, just as in human MS [25]. Finally, deletion of the Cnp1 gene coding for the myelin protein 2′-3′-cyclic nucleotide-3′-phosphodiesterase induces selective white matter degeneration, together with a vigorous spontaneous CD8 T-cell response [78]. Although these are quite different models, one may be tempted to speculate that a defect of the myelin sheath per se (possibly resulting in a specific biochemical alteration rendering the degenerated myelin even more antigenic [52], and/or involving myelin lipids [25]), rather than of the parent oligodendrocyte, may be a key factor in determining whether an adaptive immune response will be raised in the susceptible host, or not, thereby transforming a fundamentally monotonically progressive degenerative disease into a fluctuating inflammatory disorder masquerading as a primary autoimmune condition.…”

Activated immune response in an inherited leukodystrophy disease caused by the loss of oligodendrocyte gap junctions

“…T-cells but not B-cells were found in mice in which oligodendrocytes lack Pex5 (a model of adrenoleukodystrophy that has inflammation but not demyelination), although increased levels of some chemokines/cytokines were also found in affected brains (Kassmann, et al 2007). Similarly, few T-cells and no B-cells were found in mice lacking 2’,3’-phosphodiesterase (Wieser, et al 2013), a myelin-related protein. T-cell infiltration has been reported in twitcher mouse caused by a mutation in Galc gene (Ohno, et al 1993, Taniike, et al 1997).…”