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Non-classical monocytes promote neurovascular repair in cerebral small vessel disease associated with microinfarctions via CX3CR1.

ABSTRACT: Cerebral small vessel disease (cSVD) constitutes a major risk factor for dementia. Monocytes play important roles in cerebrovascular disorders. Herein, we aimed to investigate the contribution of non-classical C-X3-C motif chemokine receptor (CX3CR)1 monocytes to cSVD pathobiology and therapy. To this end, we generated chimeric mice in which CX3CR1 in non-classical monocytes was either functional (CX3CR1^GFP/+) or dysfunctional (CX3CR1^GFP/GFP). cSVD was induced in mice via the micro-occlusion of cerebral arterioles, and novel immunomodulatory approaches targeting CX3CR1 monocyte production were used. Our findings demonstrate that CX3CR1^GFP/+ monocytes transiently infiltrated the ipsilateral hippocampus and were recruited to the microinfarcts 7 days after cSVD, inversely associated with neuronal degeneration and blood-brain barrier (BBB) disruption. Dysfunctional CX3CR1^GFP/GFP monocytes failed to infiltrate the injured hippocampus and were associated with exacerbated microinfarctions and accelerated cognitive decline, accompanied with an impaired microvascular structure. Pharmacological stimulation of CX3CR1^GFP/+ monocyte generation attenuated neuronal loss and improved cognitive functions by promoting microvascular function and preserving cerebral blood flow (CBF). These changes were associated with elevated levels of pro-angiogenic factors and matrix stabilizers in the blood circulation. The results indicate that non-classical CX3CR1 monocytes promote neurovascular repair after cSVD and constitute a promising target for the development of new therapies.

SUBMITTER: Lecordier S

PROVIDER: S-EPMC10676133 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Non-classical monocytes promote neurovascular repair in cerebral small vessel disease associated with microinfarctions via CX3CR1.

Lecordier Sarah S Menet Romain R Allain Anne-Sophie AS ElAli Ayman A

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20230621 11

Cerebral small vessel disease (cSVD) constitutes a major risk factor for dementia. Monocytes play important roles in cerebrovascular disorders. Herein, we aimed to investigate the contribution of non-classical C-X3-C motif chemokine receptor (CX3CR)1 monocytes to cSVD pathobiology and therapy. To this end, we generated chimeric mice in which CX3CR1 in non-classical monocytes was either functional (CX3CR1<sup>GFP/+</sup>) or dysfunctional (CX3CR1<sup>GFP/GFP</sup>). cSVD was induced in mice via t ...[more]

PMID: 37340860

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Project description:PurposeThe pathogenesis of cerebral small vessel disease (cSVD) remains elusive despite evidence of an association between white matter hyperintensities (WMH) and endothelial cerebrovascular dysfunction. Neurovascular coupling (NVC) may be a practical alternative measure of endothelial function. We performed a systematic review of reported associations between NVC and cSVD.MethodsEMBASE and PubMed were searched for studies reporting an association between any STRIVE-defined marker of cSVD and a measure of NVC during functional magnetic resonance imaging, transcranial Doppler, positron emission tomography, near-infrared spectroscopy or single-photon emission computed tomography, from inception to November 3rd, 2022. Where quantitative data was available from studies using consistent tests and analyses, results were combined by inverse-variance weighted random effects meta-analysis.FindingsOf 29 studies (19 case-controls; 10 cohorts), 26 reported decreased NVC with increasing severity of cSVD, of which 18 were individually significant. In 28 studies reporting associations with increasing WMH, 25 reported reduced NVC. Other markers of cSVD were associated with reduced NVC in: eight of nine studies with cerebral microbleeds (six showing a significant effect); three of five studies with lacunar stroke; no studies reported an association with enlarged perivascular spaces. Specific SVD diseases were particularly associated with reduced NVC, including six out of seven studies in cerebral amyloid angiopathy and all four studies in CADASIL. In limited meta-analyses, %BOLD occipital change to a visual stimulus was consistently reduced with more severe WMH (seven studies, SMD -1.51, p < 0.01) and increasing microbleeds (seven studies, SMD -1.31, p < 0.01).Discussion and conclusionIn multiple, small studies, neurovascular coupling was reduced in patients with increasing severity of all markers of cSVD in sporadic disease, CAA and CADASIL. Cerebrovascular endothelial dysfunction, manifest as impaired NVC, may be a common marker of physiological dysfunction due to small vessel injury that can be easily measured in large studies and clinical practice.

Project description:CX3CR1+ cells play a crucial role in liver fibrosis progression. However, changes in the migratory behavior and spatial distribution of spleen-derived and hepatic CX3CR1+ cells in the fibrotic liver as well as their influence on the liver fibrosis remain unclear.MethodsThe CX3CR1GFP/+ transgenic mice and CX3CR1-KikGR transgenic mice were used to establish the CCl4-induced liver fibrosis model. Splenectomy, adoptive transfusion of splenocytes, in vivo photoconversion of splenic CX3CR1+ cells and intravital imaging were performed to study the spatial distribution, migration and movement behavior, and regulatory function of CX3CR1+ cells in liver fibrosis.ResultsIntravital imaging revealed that the CX3CR1GFP cells accumulated into the fibrotic liver and tended to accumulate towards the central vein (CV) in the hepatic lobules. Two subtypes of hepatic CX3CR1+ cells existed in the fibrotic liver. The first subtype was the interacting CX3CR1GFP cells, most of which were observed to distribute in the liver parenchyma and had a higher process velocity; the second subtype was mobile CX3CR1GFP cells, most of which were present in the hepatic vessels with a faster moving speed. Splenectomy ameliorated liver fibrosis and decreased the number of CX3CR1+ cells in the fibrotic liver. Moreover, splenectomy rearranged CX3CR1GFP cells to the boundary of the hepatic lobule, reduced the process velocity of interacting CX3CR1GFP cells and decreased the number and mobility of mobile CX3CR1GFP cells in the fibrotic liver. Transfusion of spleen-derived classical monocytes increased the process velocity and mobility of hepatic endogenous CX3CR1GFP cells and facilitated liver fibrosis progression via the production of proinflammatory and profibrotic cytokines. The photoconverted splenic CX3CR1+ KikRed+ cells were observed to leave the spleen, accumulate into the fibrotic liver and contact with hepatic CX3CR1+ KikGreen+ cells during hepatic fibrosis.ConclusionThe splenic CX3CR1+ monocytes with classical phenotype migrated from the spleen to the fibrotic liver, modifying the migratory behavior of hepatic endogenous CX3CR1GFP cells and exacerbating liver fibrosis via the secretion of cytokines. This study reveals that splenic CX3CR1+ classical monocytes are a key driver of liver fibrosis via the spleen-liver axis and may be potential candidate targets for the treatment of chronic liver fibrosis.

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Non-classical monocytes promote neurovascular repair in cerebral small vessel disease associated with microinfarctions via CX3CR1.

Publications

Non-classical monocytes promote neurovascular repair in cerebral small vessel disease associated with microinfarctions via CX3CR1.

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