The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice

Merry, Troy L.; Brooks, Anna; Masson, Stewart W.C.; Adams, Shannon; Jaiswal, Jagdish K.; Jamieson, Stephen M.F.; Shepherd, Peter R.

doi:10.1038/s41366-019-0355-7

Cited by 40 publications

(25 citation statements)

References 29 publications

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“…A study that used pharmacological intervention with 3 weeks of oral administration of PLX3397 reported that the particular CSF1R inhibitor was specific to microglia and did not impact the macrophage population in the splenic tissue [31]. On the contrary, a different study that also used PLX3397 administration for 3 weeks reported that diabetic mice exhibited a decrease in peripheral macrophages [38]. This study demonstrated that CSF1R silencing reduced inflammation in adipose tissue.…”

Section: Discussionmentioning

confidence: 84%

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

Jackson

Dumanli

Johnson

et al. 2020

J Neuroinflammation

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Introduction: Unfortunately, over 40% of stroke victims have pre-existing diabetes which not only increases their risk of stroke up to 2-6 fold, but also worsens both functional recovery and the severity of cognitive impairment. Our lab has recently linked the chronic inflammation in diabetes to poor functional outcomes and exacerbated cognitive impairment, also known as post-stroke cognitive impairment (PSCI). Although we have shown that the development of PSCI in diabetes is associated with the upregulation and the activation of pro-inflammatory microglia, we have not established direct causation between the two. To this end, we evaluated the role of microglia in the development of PSCI.Methods: At 13 weeks of age, diabetic animals received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles targeting the colony stimulating factor 1 receptor (CSF1R). After 14 days, animals were subjected to 60 min middle cerebral artery occlusion (MCAO) or sham surgery. Adhesive removal task (ART), novel object recognition (NOR), and 2-trial Y-maze were utilized to evaluate sensorimotor and cognitive function. Tissue from freshly harvested brains was analyzed by flow cytometry and immunohistochemistry.Results: CSF1R silencing resulted in a 94% knockdown of residential microglia to relieve inflammation and improve myelination of white matter in the brain. This prevented cognitive decline in diabetic animals. Conclusion: Microglial activation after stroke in diabetes may be causally related to the development of delayed neurodegeneration and PSCI.

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Section: Discussionmentioning

confidence: 84%

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

Jackson

Dumanli

Johnson

et al. 2020

J Neuroinflammation

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“…Immunoblotting was performed as previously described [ 27 ]. For tissue, snap frozen muscle was minced using scissors in a lysis buffer containing Tris–HCl 20 mM, NaCl 150 mM, EDTA 1 mM, EGTA 1 mM, Triton X 1%, NP40 1%, NaPyro 2.5 mM, β-glycerol phosphate 1 mM, Na3VO4 1 mM and NaF 100 mM, then homogenised using a Qiagen tissuelyser.…”

Section: Methodsmentioning

confidence: 99%

“…Fractionation was performed using the ThermoFisher subcellular fractionation kit for cultured cells (ThermoFisher, Waltham, MA, USA). Polymerase chain reaction (PCR) was performed as previously described [ 27 ]. RNA was extracted from frozen gastrocnemius muscle using Trizol reagent (Invitrogen, Carlsbad, CA) and a Direct-zol™ RNA MiniPrep (Zymo, Irvine, CA), and mRNA was reverse transcribed using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA).…”

Section: Methodsmentioning

confidence: 99%

β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

Masson

Sorrenson

Shepherd

et al. 2020

Molecular Metabolism

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Objective Skeletal muscle glucose disposal following a meal is mediated through insulin-stimulated movement of the GLUT4-containing vesicles to the cell surface. The highly conserved scaffold-protein β-catenin is an emerging regulator of vesicle trafficking in other tissues. Here, we investigated the involvement of β-catenin in skeletal muscle insulin-stimulated glucose transport. Methods Glucose homeostasis and transport was investigated in inducible muscle specific β-catenin knockout (BCAT-mKO) mice. The effect of β-catenin deletion and mutation of β-catenin serine 552 on signal transduction, glucose uptake and protein–protein interactions were determined in L6-G4-myc cells, and β-catenin insulin-responsive binding partners were identified via immunoprecipitation coupled to label-free proteomics. Results Skeletal muscle specific deletion of β-catenin impaired whole-body insulin sensitivity and insulin-stimulated glucose uptake into muscle independent of canonical Wnt signalling. In response to insulin, β-catenin was phosphorylated at serine 552 in an Akt-dependent manner, and in L6-G4-myc cells, mutation of β-catenin S552 impaired insulin-induced actin-polymerisation, resulting in attenuated insulin-induced glucose transport and GLUT4 translocation. β-catenin was found to interact with M-cadherin in an insulin-dependent β-catenin S552 -phosphorylation dependent manner, and loss of M-cadherin in L6-G4-myc cells attenuated insulin-induced actin-polymerisation and glucose transport. Conclusions Our data suggest that β-catenin is a novel mediator of glucose transport in skeletal muscle and may contribute to insulin-induced actin-cytoskeleton remodelling to support GLUT4 translocation.

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“…Other studies using CSF1R inhibitors to limit the development or progression of obesity show some limited effects, which are primarily explained by changes in the hypothalamus [28,30]. On the other hand, a study investigating ATMs in animals on a HFD in response to pexidartinib showed no benefit of drug treatment alone, despite substantial changes observed in the macrophage compartment within adipose tissue [45]. This observation is somewhat congruent with our data, which show no benefit by PLX5622 alone in glucose tolerance and whole-body adiposity ( Figure 1D, 1F, 1G).…”

Section: Agingmentioning

confidence: 99%

CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice

Ali

Mansour

Huang

et al. 2020

Aging

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The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice

Cited by 40 publications

References 29 publications

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice

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