Neuronal and epithelial cell rescue resolves chronic systemic inflammation in the lipid storage disorder Niemann-Pick C

Abstract

Chronic systemic inflammation is thought to be a major contributor to metabolic and neurodegenerative diseases. Since inflammatory components are shared among different disorders, targeting inflammation is an attractive option for mitigating disease. To test the significance of inflammation in the lipid storage disorder (LSD) Niemann-Pick C (NPC), we deleted the macrophage inflammatory gene Mip1a/Ccl3 from NPC diseased mice. Deletion of Ccl3 had been reported to delay neuronal loss in Sandhoff LSD mice by inhibiting macrophage infiltration. For NPC mice, in contrast, deleting Ccl3 did not retard neurodegeneration and worsened the clinical outcome. Depletion of visceral tissue macrophages also did not alter central nervous system (CNS) pathology and instead increased liver injury, suggesting a limited macrophage infiltration response into the CNS and a beneficial role of macrophage activity in visceral tissue. Prevention of neuron loss or liver injury, even at late stages in the disease, was achieved through specific rescue of NPC disease in neurons or in liver epithelial cells, respectively. Local epithelial cell correction was also sufficient to reduce the macrophage-associated pathology in lung tissue. These results demonstrate that elevated inflammation and macrophage activity does not necessarily contribute to neurodegeneration and tissue injury, and LSD defects in immune cells may not preclude an appropriate inflammatory response. We conclude that inflammation remains secondary to neuronal and epithelial cell dysfunction and does not irreversibly contribute to the pathogenic cascade in NPC disease. Without further exploration of possible beneficial roles of inflammatory mediators, targeting inflammation may not be therapeutically effective at ameliorating disease severity.

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…In addition, in microglianeuron cocultures, the presence of activated Npc1 Ϫ / Ϫ microglia did not cause neuron death ( 135 ). Consistent with the idea that infl ammation is secondary to neuron death, deletion of the macrophage infl ammatory gene Mip1a/ Ccl3 in Npc1 Ϫ / Ϫ mice did not prevent neurodegeneration ( 142 ), nor did deletion of the complement system in Npc1 Ϫ / Ϫ mice reduce neuronal death or prolong survival ( 143 ). In combination, these experiments imply that microglial activation in NPC-defi cient brains is primarily a response to neuronal death, rather than a direct cause of the neurodegeneration.…”

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“…Since the bioactive factors of CA significantly attenuate the glutamate induced excitation and oxidative stress, it is possible that the CA extract possibly ameliorate the deregulated lipid metabolism in general and cholesterol metabolism in particular, thus protecting the progressive cell damage that occurs in induced epilepsy 22 . Lipid peroxidation is a complex process generating reactive radicals, which is regarded as an etiologic or pathogenic factor in several diseases of central nervous system including epilepsy.…”

Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

“…Conversely, using the Tet-inducible Npc1 mouse model, neuron-specific NPC1 in an otherwise NPC1-deficient animal was shown to be sufficient to prevent and halt local neurodegeneration, altering neurological signs in an animal with continued systemic disease progression (Fig. 2C) (Lopez et al, 2011; Lopez et al, 2012b). These complementary results, which were obtained independently using distinct experimental methods and different mouse backgrounds, provide compelling evidence for predominant neuron-autonomous mechanisms of toxicity in NPC disease.…”

“…Other types of behavioral recordings would then be required to more accurately identify differences. The continued degeneration of other brain regions and timing of rescue would also need to be taken into account (Lopez et al, 2011; Lopez et al, 2012b). …”

“…Similarly, the cell circuitry and regulation of neurodegeneration in NPC disease mice could be studied broadly with genomic, proteomic and other approaches coupled with fine cell-specific genetic manipulations to provide insight into the control of neurodegeneration. Already, gene expression and proteomic profiles have been generated, mainly for cerebella (Liao et al, 2010; Cologna et al, 2012; Lopez et al, 2012b; Lopez et al, 2012a; Sleat et al, 2012), and a rudimentary schematic of cellular and molecular interactions in vivo can be drawn (Fig. 4A).…”