Absence of infiltrating peripheral myeloid cells in the brains of mouse models of lysosomal storage disorders

Abstract

Approximately 70 lysosomal storage diseases are currently known, resulting from mutations in genes encoding lysosomal enzymes and membrane proteins. Defects in lysosomal enzymes that hydrolyze sphingolipids have been relatively well studied. Gaucher disease is caused by the loss of activity of glucocerebrosidase, leading to accumulation of glucosylceramide. Gaucher disease exhibits a number of subtypes, with types 2 and 3 showing significant neuropathology. Sandhoff disease results from the defective activity of β-hexosaminidase, leading to accumulation of ganglioside GM2. Niemann-Pick type C disease is primarily caused by the loss of activity of the lysosomal membrane protein, NPC1, leading to storage of cholesterol and sphingosine. All three disorders display significant neuropathology, accompanied by neuroinflammation. It is commonly assumed that neuroinflammation is the result of infiltration of monocyte-derived macrophages into the brain; for instance, cells resembling lipid-engorged macrophages ('Gaucher cells') have been observed in the brain of Gaucher disease patients. We now review the evidence that inflammatory macrophages are recruited into the brain in these diseases and then go on to provide some experimental data that, at least in the three mouse models tested, monocyte-derived macrophages do not appear to infiltrate the brain. Resident microglia, which are phenotypically distinct from infiltrating macrophages, are the only myeloid population present in significant numbers within the brain parenchyma in these authentic mouse models, even during the late symptomatic stages of disease when there is substantial neuroinflammation. This article is part of the Special Issue "Lysosomal Storage Disorders".

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

“…Our study reveals pathological proteomic fingerprints of microglia in pre-symptomatic phase of NPC that associate with enhanced phagocytic uptake, increased synaptic pruning, impaired myelin turnover and its accumulation within MVBs. Microglia are responsible for the neuroinflammatory phenotype that occurs in brains of Npc1 -/mice as infiltration of peripheral macrophages could not be detected in this model (Cho, Vardi et al, 2018, Cougnoux et al, 2018. However, the contribution of microglial activation to neurodegeneration in NPC is still being discussed (Baudry et al, 2003, Gabande-Rodriguez et al, 2018, Lopez et al, 2011, Peake et al, 2011, Pressey et al, 2012.…”

Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

“…Whether the myeloid cells that do not express TMEM119 or express it at low levels in ASMko brains are DAM, monocyte-derived "microglia-like" cells or both remains to be clarified. Very recent reports suggest the absence of monocyte infiltration in the brain of mouse models for LSDs including NPC (Cho et al, 2018;Cougnoux et al, 2018). These findings would support that the TMEM119negative cells are DAM.…”

Lysosomal storage disorders: pathology within the lysosome and beyond

“…The authors focused on three LSDs where strong evidence of cytokine/chemokine expression in the brain exists; namely, neuropathic Gaucher disease, Sandhoff disease, and Niemann Pick type C. Using a flow cytometry‐based approach, where microglia were discriminated from infiltrating myeloid cells on the basis of differential CD45 expression, Cho et al . () found no evidence of peripheral myeloid influx in any of the three mouse LSD models examined. This raises the possibility that resident microglia likely contribute to neurodegenerative processes and reactive microglia have been demonstrated in almost all LSDs affecting the CNS.…”

“…in this Special Issue addresses an ongoing debate as to whether select LSDs are associated with an influx of peripheral myeloid cells into the brain, which would be expected to contribute to the neurodegenerative process (Cho et al . ). Although prior work had suggested that peripheral myeloid cells infiltrate the CNS following bone marrow transfer, this involves irradiation that is known to compromise blood–brain barrier integrity.…”

“…; Cho et al . ; Parker and Bigger ) as well as comprehensive overviews of lysosomal biology (Bajaj et al . ), CNS metabolism (McKenna et al .…”