Bone morphogenetic protein 7 polarizes THP-1 cells into M2 macrophages

Rocher, Crystal; Singla, Reetu D.; Singal, Pawan K.; Parthasarathy, S.; Singla, Dinender K.

doi:10.1139/y2012-102

Cited by 44 publications

(61 citation statements)

References 11 publications

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“…Furthermore, whether the effect of BMP7 on macrophage polarisation is either direct or indirect, in response to changes in BAT, remains to be determined. Although we could not show in our in vitro experiments a direct effect of BMP7 on M1/M2 skewing in bone-marrow derived macrophages, a recent study in which human THP-1 monocytes were treated with BMP7 demonstrated significant polarization of monocytes into M2 macrophages [30]. However, since the change in M1/M2 balance did not happen at thermoneutral temperature suggests that environmental factors are at least in part involved in the effects of BMP7 on macrophage polarisation.…”

Section: Discussioncontrasting

confidence: 84%

BMP7 Activates Brown Adipose Tissue and Reduces Diet-Induced Obesity Only at Subthermoneutrality

et al. 2013

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Background/AimsBrown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP-1 and is a promising target to combat hyperlipidemia and obesity. BAT is densely innervated by the sympathetic nervous system, which increases BAT differentiation and activity upon cold exposure. Recently, Bone Morphogenetic Protein 7 (BMP7) was identified as an inducer of BAT differentiation. We aimed to elucidate the role of sympathetic activation in the effect of BMP7 on BAT by treating mice with BMP7 at varying ambient temperature, and assessed the therapeutic potential of BMP7 in combating obesity.Methods and ResultsHigh-fat diet fed lean C57Bl6/J mice were treated with BMP7 via subcutaneous osmotic minipumps for 4 weeks at 21°C or 28°C, the latter being a thermoneutral temperature in which sympathetic activation of BAT is largely diminished. At 21°C, BMP7 increased BAT weight, increased the expression of Ucp1, Cd36 and hormone-sensitive lipase in BAT, and increased total energy expenditure. BMP7 treatment markedly increased food intake without affecting physical activity. Despite that, BMP7 diminished white adipose tissue (WAT) mass, accompanied by increased expression of genes related to intracellular lipolysis in WAT. All these effects were blunted at 28°C. Additionally, BMP7 resulted in extensive ‘browning’ of WAT, as evidenced by increased expression of BAT markers and the appearance of whole clusters of brown adipocytes via immunohistochemistry, independent of environmental temperature. Treatment of diet-induced obese C57Bl6/J mice with BMP7 led to an improved metabolic phenotype, consisting of a decreased fat mass and liver lipids as well as attenuated dyslipidemia and hyperglycemia.ConclusionTogether, these data show that BMP7-mediated recruitment and activation of BAT only occurs at subthermoneutral temperature, and is thus likely dependent on sympathetic activation of BAT, and that BMP7 may be a promising tool to combat obesity and associated disorders.

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Section: Discussioncontrasting

confidence: 84%

BMP7 Activates Brown Adipose Tissue and Reduces Diet-Induced Obesity Only at Subthermoneutrality

et al. 2013

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“…BMP6 regulates expression of inflammatory markers such as IL-6, IL-1β, and nitric oxide synthase in macrophages [78–80]. In addition, more recent studies indicate that BMP exposure particularly leads to the M2 or anti-inflammatory phenotype of the macrophages promoting tissue repair [81–84]. Microglia are descendants of immature macrophages and are thought to act as macrophages in disease and injury states [85].…”

Section: Discussionmentioning

confidence: 99%

Microglia activation is essential for BMP7-mediated retinal reactive gliosis

Dharmarajan

Fisk

Sorenson

et al. 2017

J Neuroinflammation

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BackgroundOur previous studies have shown that BMP7 is able to trigger activation of retinal macroglia. However, these studies showed the responsiveness of Müller glial cells and retinal astrocytes in vitro was attenuated in comparison to those in vivo, indicating other retinal cell types may be mediating the response of the macroglial cells to BMP7. In this study, we test the hypothesis that BMP7-mediated gliosis is the result of inflammatory signaling from retinal microglia.MethodsAdult mice were injected intravitreally with BMP7 and eyes harvested 1, 3, or 7 days postinjection. Some mice were treated with PLX5622 (PLX) to ablate microglia and were subsequently injected with control or BMP7. Processed tissue was analyzed via immunofluorescence, RT-qPCR, or ELISA. In addition, cultures of retinal microglia were treated with vehicle, lipopolysaccharide, or BMP7 to determine the effects of BMP7-isolated cells.ResultsMice injected with BMP7 showed regulation of various inflammatory markers at the RNA level, as well as changes in microglial morphology. Isolated retinal microglia also showed an upregulation of BMP-signaling components following treatment. In vitro treatment of retinal astrocytes with conditioned media from activated microglia upregulated RNA levels of gliosis markers. In the absence of microglia, the mouse retina showed a subdued gliosis and inflammatory response when exposed to BMP7.ConclusionsGliosis resulting from BMP7 is mediated through an inflammatory response from retinal microglia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0855-0) contains supplementary material, which is available to authorized users.

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“…The slides were counterstained with DAPI, and then were then incubated at 4°C for 24 hours. Cells were photomicrographed using confocal microscopy and cell counting was preformed, as we reported previously (Rocher et al 2012;Singla et al 2014).…”

Section: Immunocytochemistrymentioning

confidence: 99%

“…These pro-inflammatory cytokines include IL-6, MCP-1, and TNF-α (Kleemann et al 2008;Outtz et al 2010;Singla et al 2014). Conversely, M2 macrophages are anti-inflammatory, and aid in the repair of damaged tissue, making them a potential candidate for therapeutic options (Rocher et al 2012;Singla et al 2016). Secreted from M2 macrophages are the anti-inflammatory cytokines IL-10 and IL-1RA, and show an increase in the expression of Arginase-1 enzyme important in reducing harmful nitric oxide production (Kleemann et al 2008;Outtz et al 2010;Singla et al 2014).…”

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confidence: 99%

Primary human monocytes differentiate into M2 macrophages and involve Notch-1 pathway

Singla

Wang

Singla

2017

Can. J. Physiol. Pharmacol.

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The current study investigates whether inhibiting the Notch-1 signaling pathway in primary human monocytes enhances M2 macrophage differentiation. We generated primary human monocytes cell culture model to understand the effect of Notch-1 signaling pathway. Monocytes were treated with Notch-1inhibitors DAPT or siRNA. Our data show that there was a significant increase in the M1 macrophage population demonstrated by iNOS marker in the primary human monocytes treated with apoptotic conditioned medium (ACM). Next, the levels of pro-inflammatory cytokines IL-6, and MCP-1, as well as TNF-α increased in ACM media (p < 0.05). Furthermore, M1 macrophages and pro-inflammatory cytokines were reduced following DAPT or siRNA treatment. Comparatively, there was a significant increase in M2 macrophages as demonstrated by an increase in CD206 and arginase-1 positive cells treated with DAPT or siRNA (p < 0.05). Furthermore, a significant increase in the associated anti-inflammatory cytokines IL-10 and IL-1RA was also observed with respect to control groups (p < 0.05). We conclude that blocking the Notch-1 pathway with DAPT or siRNA attenuates pro-inflammatory cytokines, enhances M2 macrophage differentiation, and increases anti-inflammatory cytokines in primary human monocytes. As a result, Notch-1 pathway inhibition has potential therapeutic applications of inflammatory disease.

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Bone morphogenetic protein 7 polarizes THP-1 cells into M2 macrophages

Cited by 44 publications

References 11 publications

BMP7 Activates Brown Adipose Tissue and Reduces Diet-Induced Obesity Only at Subthermoneutrality

BMP7 Activates Brown Adipose Tissue and Reduces Diet-Induced Obesity Only at Subthermoneutrality

Microglia activation is essential for BMP7-mediated retinal reactive gliosis

Primary human monocytes differentiate into M2 macrophages and involve Notch-1 pathway

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