Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease

Fuhrmann, Martin; Bittner, Tobias; Jung, Christian; Burgold, Steffen; Page, Richard; Mitteregger, Gerda; Haass, Christian; LaFerla, Frank M.; Kretzschmar, Hans A.; Herms, Jochen

doi:10.1038/nn.2511

Cited by 477 publications

(386 citation statements)

References 15 publications

(16 reference statements)

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“…In this paper, we report a previously undescribed antifibrotic effect of CX 3 CR1: it reduced the inflammation-induced proliferation of TGF-b-producing renal macrophages, which are critically important in experimental kidney fibrosis (15)(16)(17)(18). This finding was unexpected, given the proinflammatory and profibrotic properties of CX 3 CR1 not only in diseases of the kidney (3,49,54,(57)(58)(59)65), but also of the lung (75), liver (50), intestine (28), skin (55), arteriosclerotic vessels (76), and the CNS (33). CX 3 CR1 has been shown to contribute to the inflammatory recruitment of monocytes from the circulation into all these organs (44).…”

Section: Discussionmentioning

confidence: 99%

“…The chemokine receptor CX 3 CR1, also known as fractalkine receptor, is ubiquitously expressed on most tissue macrophages and DCs but does not play a major role for their ontogeny, homeostatic migration, or colonization of tissues with resident phagocytes (26,27), except kidney DCs (3) and intestinal macrophages (28)(29)(30). There is evidence that the survival of monocytes and tissue macrophages depends on CX 3 CR1 (31)(32)(33), and this required interaction with cell surface-bound CX 3 CL1 (34). CX 3 CL1 + cells have been shown to be present within glomeruli and in the tubular compartment (35), but their exact identity is unclear.…”

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confidence: 99%

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CX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages

Engel

Krause

Snelgrove

et al. 2015

The Journal of Immunology

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A dense network of macrophages and dendritic cells (DC) expressing the chemokine receptor CX3CR1 populates most tissues. We recently reported that CX3CR1 regulates the abundance of CD11c+ DC in the kidney and thereby promotes renal inflammation in glomerulonephritis. Given that chronic inflammation usually causes fibrosis, we hypothesized that CX3CR1 deficiency should attenuate renal fibrosis. However, when we tested this hypothesis using the DC-independent murine fibrosis model of unilateral ureteral obstruction, kidney fibrosis was unexpectedly more severe, despite less intrarenal inflammation. Two-photon imaging and flow cytometry revealed in kidneys of CX3CR1-deficient mice more motile Ly6C/Gr-1+ macrophages. Flow cytometry verified that renal macrophages were more abundant in the absence of CX3CR1 and produced more of the key profibrotic mediator, TGF-β. Macrophages accumulated because of higher intrarenal proliferation, despite reduced monocyte recruitment and higher signs of apoptosis within the kidney. These findings support the theory that tissue macrophage numbers are regulated through local proliferation and identify CX3CR1 as a regulator of such proliferation. Thus, CX3CR1 inhibition should be avoided in DC-independent inflammatory diseases because it may promote fibrosis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

CX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages

Engel

Krause

Snelgrove

et al. 2015

The Journal of Immunology

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“…8 Moreover, recent studies demonstrating that variants of TREM2 and CD33, two receptors expressed in microglial cells, increase the risk for late-onset AD 21,22 have refocused the spotlight on microglia as a major contributing factor in AD. Although multiple preclinical evidence indicates that microglia activation promotes neuronal dysfunction and neuron elimination 23,24 and accelerates AD progression, 19,25,26 the molecular mechanisms by which microglia exert neurotoxicity remain largely unknown.…”

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confidence: 99%

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

et al. 2013

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Alzheimer's disease (AD) is characterized by extracellular amyloid-b (Ab) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Ab species, rather than insoluble fibrils, are the most toxic forms of Ab. Preventing soluble Ab formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Ab species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Ab forms trafficked to MVs after Ab internalization into microglia. MV neurotoxicity was neutralized by the Ab-interacting protein PrP and anti-Ab antibodies, which prevented binding to neurons of neurotoxic soluble Ab species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease. Cell Death and Differentiation (2014) 21, 582-593; doi:10.1038/cdd.2013.180; published online 13 December 2013Alzheimer's disease (AD) is the major cause of dementia in humans. Neuronal loss and cognitive decline occurring in AD patients are traditionally linked to the accumulation in the brain of extracellular plaques consisting of short amyloid-b (Ab) peptides of 39-42 amino acids, generated by amyloidogenic cleavage of the amyloid precursor protein. 1 Among Ab peptides, Ab 1-42 and pyroglutamate-modified Ab very rapidly aggregate and initiate the complex multistep process that leads to mature fibrils and plaque. 2,3 Although association of amyloid plaques with AD has long been assumed, Ab load does not correlate with neuronal loss 4,5 and high plaque burden does not necessarily lead to dementia in humans. 6,7 Accordingly, recent evidence clearly showed that the amyloid load reaches a plateau early after the onset of clinical symptoms in AD patients 8 and does not substantially increase in size during clinical progression. 9 These observations agree with the current view that small, soluble pre-fibrillar Ab species, rather than plaques formed by insoluble Ab fibrils, are the most toxic forms of Ab. 10 These cause synaptic dysfunction and spine loss, and correlate most closely with the severity of human AD. 5,8,11 Recent biochemical studies indicated that natural sphingolipids and gangliosides, whose metabolism has been shown to be altered in AD patients, 12 destabilize and rapidly resolubilize long Ab fibrils to neurotoxic species. 13 These studies also showed that phospholipids stabilize toxic oligomers...

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“…These findings were confirmed in additional AD mouse models [96,97]. Using in vivo 2-photon imaging, Fuhrmann et al [98] showed that in the 5XFAD model of AD, homozygous loss of CX3CR1 impaired microglia recruitment to areas of neuronal death. This resulted in reduced neurodegeneration, again improving pathology.…”

Section: Cx3cr1/cx3cl1mentioning

confidence: 83%

The Evolving Biology of Microglia in Alzheimer's Disease

2015

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Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease

Cited by 477 publications

References 15 publications

CX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages

CX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

The Evolving Biology of Microglia in Alzheimer's Disease

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