Microglia pre-activation and neurodegeneration precipitate neuroinflammation without exacerbating tissue injury in experimental autoimmune encephalomyelitis

Abstract

Human inflammatory or neurodegenerative diseases, such as progressive multiple sclerosis (MS), occur on a background of age-related microglia activation and iron accumulation as well as pre-existing neurodegeneration. Most experimental models for CNS diseases, however, are induced in rodents, which are naturally characterized by a homeostatic microglia phenotype, low cellular iron load and absence of neurodegeneration. Here, we show that naïve LEWzizi rats – Lewis rats with a zitter rat background – show a spontaneous phenotype partly mimicking the changes seen in human aging and particularly in the normal-appearing white and grey matter of patients with progressive MS. Using this model system, we further aimed to investigate (i) whether the acute monophasic MS model experimental autoimmune encephalomyelitis (EAE) transforms into chronic progressive disease and (ii) whether EAE-induced neuroinflammation and tissue damage aggravate on the LEWzizi background. We found that the pre-existing LEWzizi-specific pathology precipitated EAE-related neuroinflammation into forebrain areas, which are devoid of EAE lesions in normal Lewis rats. However, EAE-related tissue damage was neither modified by the LEWzizi-specific pathology nor did EAE-induced neuroinflammation modify the LEWzizi-related pathological process. Our data indicate that the interaction between pre-activated microglia and CD4+ autoreactive T cells during the induction and propagation of tissue damage in the CNS is limited.Electronic supplementary materialThe online version of this article (10.1186/s40478-019-0667-9) contains supplementary material, which is available to authorized users.

Iron accumulation in the choroid plexus, ependymal cells and CNS parenchyma in a rat strain with low‐grade haemolysis of fragile macrocytic red blood cells

“…As we have shown previously, iron levels in ageing LEWzizi rats increase more pronouncedly compared with age-matched wild-type Lewis rats (32). Here, we deepen the topographical analyses of CNS iron accumulation ( Figure 3A-C).…”

“…The role of iron as an amplifier of tissue damage has gained increasing interest in various neurological diseases (41); however, the translatability of experimental rodent data to neuroinflammation and neurodegeneration in the human CNS is limited (29). In the current work, we characterised iron accumulation in the brain of LEWzizi rats, which descend from zitter (zi/zi) rats (30,31) and present with abnormally high iron levels in the CNS (32). There, iron accumulates with age mainly in oligodendrocytes and myelin sheaths in a similar anatomical and cellular distribution as observed in aged humans (29,32).…”

“…Experimental rodent studies on iron overload are limited by intrinsically low CNS iron levels in these models, which hardly increase with age (29). Rats harbouring a spontaneous mutation in the attractin (Atrn) gene (LEWzizi and zitter (zi/zi) rats) show abnormally high iron levels in the CNS parenchyma, as we and others have shown before (30)(31)(32). Using this rat model, we aimed at investigating changes in iron loading in the ventricular system including choroid plexus, CSF and ependyma.…”

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging

“…Currently, TSPO PET imaging is the most widely used in vivo method for inferring on the status of microglial activation. Direct evidence for an innate inflammatory response in AD was described nearly 20 years ago 70 , and subsequent studies have demonstrated neuroinflammation in PD 71 , ALS 72 , 73 , MS 74 , major depressive disorder (MDD) 30 , obsessive compulsive disorder (OCD) 75 and a growing number of other nervous system pathologies. Previous studies in rodents after lipopolysaccharide (LPS) or toxins have also reported that dramatic upregulation of TSPO levels are correlated with microglial activation in response to brain injury or neuroinflammation 76 , 77 although in postmortem investigations in humans both activated microglia and astroglia may overexpress TSPO 27 , 28 .…”

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

“…Neither of these conditions had an effect on EAE related inflammation nor on the neurodegenerative process due to the pre‐existing microglia activation (Rubino et al, ). In a further study, EAE was induced by active immunization or passive T‐cell transfer in an experimental model, which was characterized by microglia activation, accelerated iron accumulation in the brain, and progressive neurodegeneration (Wimmer et al, ), a pathological scenario which closely reflects the tissue changes seen in the progressive stage of multiple sclerosis (Mahad, Trapp, & Lassmann, ). Also in this model, the pathology of EAE was not modified by the pre‐existing microglia activation, nor was the progressive neurodegenerative phenotype altered by the inflammatory process of EAE.…”