Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation

Microglia are the first responders to intracerebral hemorrhage, but their precise role in intracerebral hemorrhage remains to be defined. Microglia are the only type of brain cells expressing the colony-stimulating factor 1 receptor, a key regulator for myeloid lineage cells. Here, we determined the effects of a colony-stimulating factor 1 receptor inhibitor (PLX3397) on microglia and the outcome in the context of experimental mouse intracerebral hemorrhage. We show that PLX3397 effectively depleted microglia, and the depletion of microglia was sustained after intracerebral hemorrhage. Importantly, colony-stimulating factor 1 receptor inhibition attenuated neurodeficits and brain edema in two experimental models of intracerebral hemorrhage induced by injection of collagenase or autologous blood. The benefit of colony-stimulating factor 1 receptor inhibition was associated with reduced leukocyte infiltration in the brain and improved blood–brain barrier integrity after intracerebral hemorrhage, and each observation was independent of lesion size or hematoma volume. These results demonstrate that suppression of colony-stimulating factor 1 receptor signaling ablates microglia and confers protection after intracerebral hemorrhage.

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Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization

Neuro-Oncology ◽

10.1093/neuonc/nov272 ◽

2015 ◽

Vol 18 (6) ◽

pp. 797-806 ◽

Cited By ~ 83

Author(s):

Jason H. Stafford ◽

Takahisa Hirai ◽

Lei Deng ◽

Sophia B. Chernikova ◽

Kimiko Urata ◽

...

Keyword(s):

Myeloid Cell ◽

Colony Stimulating Factor ◽

Cell Recruitment ◽

Receptor Inhibition ◽

Stimulating Factor

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[Corrigendum] Colony‑stimulating factor 1 receptor inhibition blocks macrophage infiltration and endometrial cancer cell proliferation

Molecular Medicine Reports ◽

10.3892/mmr.2020.11197 ◽

2020 ◽

Vol 22 (2) ◽

pp. 1663-1663

Author(s):

Fu Hua ◽

Ye Tian ◽

Yingchun Gao ◽

Changhua Li ◽

Xiaoping Liu

Keyword(s):

Cell Proliferation ◽

Endometrial Cancer ◽

Cancer Cell ◽

Macrophage Infiltration ◽

Cancer Cell Proliferation ◽

Colony Stimulating Factor ◽

Endometrial Cancer Cell ◽

Receptor Inhibition ◽

Stimulating Factor

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Colony‑stimulating factor 1 receptor inhibition blocks macrophage infiltration and endometrial cancer cell proliferation

Molecular Medicine Reports ◽

10.3892/mmr.2019.9963 ◽

2019 ◽

Cited By ~ 1

Author(s):

Fu Hua ◽

Ye Tian ◽

Yingchun Gao ◽

Changhua Li ◽

Xiaoping Liu

Keyword(s):

Cell Proliferation ◽

Endometrial Cancer ◽

Cancer Cell ◽

Macrophage Infiltration ◽

Cancer Cell Proliferation ◽

Colony Stimulating Factor ◽

Endometrial Cancer Cell ◽

Receptor Inhibition ◽

Stimulating Factor

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Neutrophil and Macrophage Cell Surface Colony-Stimulating Factor 1 Shed by ADAM17 Drives Mouse Macrophage Proliferation in Acute and Chronic Inflammation

Molecular and Cellular Biology ◽

10.1128/mcb.00103-18 ◽

2018 ◽

Vol 38 (17) ◽

Cited By ~ 6

Author(s):

Jingjing Tang ◽

Jeremy M. Frey ◽

Carole L. Wilson ◽

Angela Moncada-Pazos ◽

Clémence Levet ◽

...

Keyword(s):

Cell Surface ◽

Chronic Inflammation ◽

Inflammatory Diseases ◽

Colony Stimulating Factor ◽

Inflammatory Conditions ◽

Acute Peritonitis ◽

Elevated Expression ◽

Macrophage Colony ◽

Acute And Chronic Inflammation ◽

Stimulating Factor

ABSTRACT Macrophages are prominent cells in acute and chronic inflammatory diseases. Recent studies highlight a role for macrophage proliferation post-monocyte recruitment under inflammatory conditions. Using an acute peritonitis model, we identify a significant defect in macrophage proliferation in mice lacking the leukocyte transmembrane protease ADAM17. The defect is associated with decreased levels of macrophage colony-stimulating factor 1 (CSF-1) in the peritoneum and is rescued by intraperitoneal injection of CSF-1. Cell surface CSF-1 (csCSF-1) is one of the substrates of ADAM17. We demonstrate that both infiltrated neutrophils and macrophages are major sources of csCSF-1. Furthermore, acute shedding of csCSF-1 following neutrophil extravasation is associated with elevated expression of iRhom2, a member of the rhomboid-like superfamily, which promotes ADAM17 maturation and trafficking to the neutrophil surface. Accordingly, deletion of hematopoietic iRhom2 is sufficient to prevent csCSF-1 release from neutrophils and macrophages and to prevent macrophage proliferation. In acute inflammation, csCSF-1 release and macrophage proliferation are self-limiting due to transient leukocyte recruitment and temporally restricted csCSF-1 expression. In chronic inflammation, such as atherosclerosis, the ADAM17-mediated lesional macrophage proliferative response is prolonged. Our results demonstrate a novel mechanism whereby ADAM17 promotes macrophage proliferation in states of acute and chronic inflammation.

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Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice

Journal of Neuroinflammation ◽

10.1186/s12974-015-0366-9 ◽

2015 ◽

Vol 12 (1) ◽

Cited By ~ 183

Author(s):

Nabil N. Dagher ◽

Allison R. Najafi ◽

Kara M. Neely Kayala ◽

Monica R. P. Elmore ◽

Terra E. White ◽

...

Keyword(s):

Colony Stimulating Factor ◽

Receptor Inhibition ◽

Stimulating Factor

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CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01204-8 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Chritica Lodder ◽

Isabelle Scheyltjens ◽

Ilie Cosmin Stancu ◽

Pablo Botella Lucena ◽

Manuel Gutiérrez de Ravé ◽

...

Keyword(s):

Neurofibrillary Tangles ◽

Microglial Activation ◽

Amyloid Plaques ◽

Colony Stimulating Factor ◽

Tau Pathology ◽

Preclinical Models ◽

Receptor Inhibition ◽

Single Cell Rna Sequencing ◽

The Brain ◽

Stimulating Factor

AbstractAlzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of AD. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

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