Astrocyte-Derived CCL2 is Associated with M1 Activation and Recruitment of Cultured Microglial Cells

He, Min; Dong, Huijuan; Huang, Ya‐Hui; Lu, Shunmei; Zhang, Shu; Qian, Yanning; Jin, Wenjie

doi:10.1159/000443040

Cited by 70 publications

(56 citation statements)

References 28 publications

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“…A further mechanism elucidated by this study is that Ccl2 induces macrophage polarization to the M1 phenotype through its receptor, Ccr2. The Ccl2/Ccr2 pathway has been reported to skew macrophage polarization at the transcriptomic and functional level in human and mouse macrophages (46)(47)(48)(49). Our studies here provide evidence that Ccl2 can induce Ccr2-dependent expression of M1-associated genes, but not M2-associated genes, and further suggested that the Ccl2/Ccr2 pathway may be associated with M1 macrophage polarization.…”

Section: Discussionsupporting

confidence: 62%

miR-511-3p protects against cockroach allergen–induced lung inflammation by antagonizing CCL2

Danh¹,

Mu²,

Xia³

et al. 2019

JCI Insight

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Section: Discussionsupporting

confidence: 62%

miR-511-3p protects against cockroach allergen–induced lung inflammation by antagonizing CCL2

Danh¹,

Mu²,

Xia³

et al. 2019

JCI Insight

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“…A similar role for astrocytes has been theorized in the brain metastatic microenvironment but remains largely unexplored 54 . Here, we establish that melanoma-secreted Aβ directly suppresses astrocyte secretion of several cytokines that recruit and activate microglia, such as CCL2, a potent chemoattractant that polarizes microglia to a pro-inflammatory, anti-tumorigenic M1 phenotype 41 . Furthermore, we demonstrate that melanoma-secreted Aβ inhibits microglial phagocytosis of melanoma cells.…”

Section: Discussionmentioning

confidence: 85%

“…Several of the identified astrocyte-secreted cytokines have documented roles in microglial chemotaxis 40 , activation 31 , and M1 polarization 41 . We therefore sought to examine the effect of melanoma-secreted Aβ on the recruitment of microglia to the metastatic site.…”

Section: Mainmentioning

confidence: 99%

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Kleffman

Levinson

Wong

et al. 2019

Preprint

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26Brain metastasis is a significant cause of morbidity and mortality in multiple cancer 27 types and represents an unmet clinical need. The mechanisms that mediate metastatic 28 cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the 29 highest rate of brain metastasis among common cancer types, is an ideal model to 30 study how cancer cells adapt to the brain parenchyma. We performed unbiased 31 proteomics analysis of melanoma short-term cultures, a novel model for the study of 32 brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative 33 pathologies are differentially expressed in melanoma cells explanted from brain 34 metastases compared to those derived from extracranial metastases. This raised the 35 exciting hypothesis that molecular pathways implicated in neurodegenerative disorders 36 are critical for metastatic adaptation to the brain. 37 38Here, we show that melanoma cells require amyloid beta (Ab), a polypeptide heavily 39 implicated in Alzheimer's disease, for growth and survival in the brain parenchyma. 40Melanoma cells produce and secrete Ab, which activates surrounding astrocytes to a 41 pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that 42 pharmacological inhibition of Ab decreases brain metastatic burden. 43 44Our results reveal a mechanistic connection between brain metastasis and Alzheimer's 45 disease -two previously unrelated pathologies, establish Ab as a promising therapeutic 46 target for brain metastasis, and demonstrate suppression of neuroinflammation as a 47 critical feature of metastatic adaptation to the brain parenchyma. 48 49 3 Main 50 51Brain metastasis is the most common form of adult intracranial malignancy 1 and results 52 in severe morbidity and mortality. 40-75% of Stage IV melanoma patients develop brain 53 metastasis 2,3 , reflecting melanoma's striking ability to colonize the brain. Brain 54 metastases are less responsive than extracranial metastases to current cancer 55 therapies 4-6 , and the majority of patients succumb to disease in less than one year 7 . 56 Furthermore, patients with brain metastasis are often excluded from clinical trials and 57 urgently need new clinical options. In recent years, research has started to elucidate the 58 molecular mechanisms contributing to the multi-step process of brain metastasis. Most 59 findings have focused on cancer extravasation across the blood-brain barrier (BBB), 60 which cannot be leveraged therapeutically given that the vast majority of brain 61 metastasis patients will present with extravasated cancer cells at the time of cancer 62 diagnosis. The main bottleneck in the brain metastatic process has been shown to be 63 the successful expansion of a single cell in the brain parenchyma to form a macro-64 metastasis 8 . Recent studies have begun to demonstrate the role of the brain 65 microenvironment in this process. In particular, reactive astrocytes have been shown to 66 interact with cancer cells in the brain 9,10 and exhibit both pro-and anti-...

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“…In an in vitro study, CCL2 released from primary astrocytes contributed to M1 microglial polarization 191 . In mice with collagenase-induced ICH, a lack of CCL2 or CCR2 decreased the haematoma volume early after collagenase-induced ICH but resulted in delayed recovery from ICH 112 ; these changes correlated with decreases in microglial activation and iNOS expression 112 .…”

Section: Microglial Interactions With Other Cellsmentioning

confidence: 99%

Modulators of microglial activation and polarization after intracerebral haemorrhage

et al. 2017

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Intracerebral haemorrhage (ICH) is the most lethal subtype of stroke but currently lacks effective treatment. Microglia are among the first non-neuronal cells on the scene during the innate immune response to ICH. Microglia respond to acute brain injury by becoming activated and developing classic M1-like (proinflammatory) or alternative M2-like (anti-inflammatory) phenotypes. This polarization implies as yet unrecognized actions of microglia in ICH pathology and recovery, perhaps involving microglial production of proinflammatory or anti-inflammatory cytokines and chemokines. Furthermore, alternatively activated M2-like microglia might promote phagocytosis of red blood cells and tissue debris, a major contribution to haematoma clearance. Interactions between microglia and other cells modulate microglial activation and function, and are also important in ICH pathology. This Review summarizes key studies on modulators of microglial activation and polarization after ICH, including M1-like and M2-like microglial phenotype markers, transcription factors and key signalling pathways. Microglial phagocytosis, haematoma resolution, and the potential crosstalk between microglia and T lymphocytes, neurons, astrocytes, and oligodendrocytes in the ICH brain are described. Finally, the clinical and translational implications of microglial polarization in ICH are presented, including the evidence that therapeutic approaches aimed at modulating microglial function might mitigate ICH injury and improve brain repair.

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Astrocyte-Derived CCL2 is Associated with M1 Activation and Recruitment of Cultured Microglial Cells

Cited by 70 publications

References 28 publications

miR-511-3p protects against cockroach allergen–induced lung inflammation by antagonizing CCL2

miR-511-3p protects against cockroach allergen–induced lung inflammation by antagonizing CCL2

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Modulators of microglial activation and polarization after intracerebral haemorrhage

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