Involvement of IGF-1 and Akt in M1/M2 activation state in bone marrow-derived macrophages

Barrett, James W.; Minogue, Aedín M.; Falvey, Aidan; Lynch, Marina A.

doi:10.1016/j.yexcr.2015.05.015

Cited by 51 publications

(43 citation statements)

References 30 publications

(44 reference statements)

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“…STAT1 is elevated following stimulation with pro-inflammatory cytokines and/or TLR agonists [5, 8]. Here, we demonstrate that STAT1 phosphorylation is significantly elevated in WT and NOX2 −/− BMDMs in response to LPS/IL-4 stimulation ( P < 0.001; ANOVA; Fig.…”

Section: Resultssupporting

confidence: 52%

“…BMDMs were isolated from the marrow of the femurs and tibias of uninjured adult WT and NOX2 −/− male mice as previously described [8]. Briefly, following terminal anesthesia (100 mg/kg sodium pentobarbital, I.P.…”

Section: Methodsmentioning

confidence: 99%

“…Stimulation of macrophages with interleukin-4 (IL-4) upregulates the expression of markers of the anti-inflammatory phenotype—effects mediated in part through activation of STAT6 [6]. Other inflammatory mediators such as interleukin-10 (IL-10) [7] and insulin-stimulating growth factor-1 (IGF-1) [8] may also activate the anti-inflammatory phenotype.…”

Section: Introductionmentioning

confidence: 99%

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NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury

Barrett

Henry

Villapol

et al. 2017

J Neuroinflammation

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BackgroundNADPH oxidase (NOX2) is an enzyme system that generates reactive oxygen species (ROS) in microglia and macrophages. Excessive ROS production is linked with neuroinflammation and chronic neurodegeneration following traumatic brain injury (TBI). Redox signaling regulates macrophage/microglial phenotypic responses (pro-inflammatory versus anti-inflammatory), and NOX2 inhibition following moderate-to-severe TBI markedly reduces pro-inflammatory activation of macrophages/microglia resulting in concomitant increases in anti-inflammatory responses. Here, we report the signaling pathways that regulate NOX2-dependent macrophage/microglial phenotype switching in the TBI brain.MethodsBone marrow-derived macrophages (BMDMs) prepared from wildtype (C57Bl/6) and NOX2 deficient (NOX2−/−) mice were treated with lipopolysaccharide (LPS; 10 ng/ml), interleukin-4 (IL-4; 10 ng/ml), or combined LPS/IL-4 to investigate signal transduction pathways associated with macrophage activation using western immunoblotting and qPCR analyses. Signaling pathways and activation markers were evaluated in ipsilateral cortical tissue obtained from adult male wildtype and NOX2−/− mice that received moderate-level controlled cortical impact (CCI). A neutralizing anti-IL-10 approach was used to determine the effects of IL-10 on NOX2-dependent transitions from pro- to anti-inflammatory activation states.ResultsUsing an LPS/IL-4-stimulated BMDM model that mimics the mixed pro- and anti-inflammatory responses observed in the injured cortex, we show that NOX2−/− significantly reduces STAT1 signaling and markers of pro-inflammatory activation. In addition, NOX2−/− BMDMs significantly increase anti-inflammatory marker expression; IL-10-mediated STAT3 signaling, but not STAT6 signaling, appears to be critical in regulating this anti-inflammatory response. Following moderate-level CCI, IL-10 is significantly increased in microglia/macrophages in the injured cortex of NOX2−/− mice. These changes are associated with increased STAT3 activation, but not STAT6 activation, and a robust anti-inflammatory response. Neutralization of IL-10 in NOX2−/− BMDMs or CCI mice blocks STAT3 activation and the anti-inflammatory response, thereby demonstrating a critical role for IL-10 in regulating NOX2-dependent transitions between pro- and anti-inflammatory activation states.ConclusionsThese studies indicate that following TBI NOX2 inhibition promotes a robust anti-inflammatory response in macrophages/microglia that is mediated by the IL-10/STAT3 signaling pathway. Thus, therapeutic interventions that inhibit macrophage/microglial NOX2 activity may improve TBI outcomes by not only limiting pro-inflammatory neurotoxic responses, but also enhancing IL-10-mediated anti-inflammatory responses that are neuroprotective.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0843-4) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury

Barrett

Henry

Villapol

et al. 2017

J Neuroinflammation

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“…Interestingly, macrophages express high levels of IGF-IR [22]. Moreover, both IGF-I, through PI3K/Akt signaling pathway [23], and HGF, through ERK1/2-dependent IL-10 induction [24], were found involved in the M1-to-M2 phenotype change. Thus our results are consistent with the literature suggesting an immunomodulatory role played by MSCs in the phenotype of hMø.…”

Section: Discussionmentioning

confidence: 99%

Involvement of hepatic macrophages in the antifibrotic effect of IGF-I-overexpressing mesenchymal stromal cells

et al. 2016

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BackgroundCirrhosis is a major health problem worldwide and new therapies are needed. Hepatic macrophages (hMø) have a pivotal role in liver fibrosis, being able to act in both its promotion and its resolution. It is well-known that mesenchymal stromal cells (MSCs) can modulate the immune/inflammatory cells. However, the effects of MSCs over hMø in the context of liver fibrosis remain unclear. We previously described evidence of the antifibrotic effects of in vivo applying MSCs, which were enhanced by forced overexpression of insulin-like growth factor 1 (AdIGF-I-MSCs). The aim of this work was to analyze the effect of MSCs on hMø behavior in the context of liver fibrosis resolution.MethodsFibrosis was induced in BALB/c mice by chronic administration of thioacetamide (8 weeks). In vivo gene expression analyses, in vitro experiments using hMø isolated from the nonparenchymal liver cells fraction, and in vivo experiments with depletion of Mø were performed.ResultsOne day after treatment, hMø from fibrotic livers of MSCs-treated animals showed reduced pro-inflammatory and pro-fibrogenic gene expression profiles. These shifts were more pronounced in AdIGF-I-MSCs condition. This group showed a significant upregulation in the expression of arginase-1 and a higher downregulation of iNOS expression thus suggesting decreased levels of oxidative stress. An upregulation in IGF-I and HGF expression was observed in hMø from AdIGF-I-MSCs-treated mice suggesting a restorative phenotype in these cells. Factors secreted by hMø, preconditioned with MSCs supernatant, caused a reduction in the expression levels of hepatic stellate cells pro-fibrogenic and activation markers. Interestingly, hMø depletion abrogated the therapeutic effect achieved with AdIGF-I-MSCs therapy. Expression profile analyses for cell cycle markers were performed on fibrotic livers after treatment with AdIGF-I-MSCs and showed a significant regulation in genes related to DNA synthesis and repair quality control, cell cycle progression, and DNA damage/cellular stress compatible with early induction of pro-regenerative and hepatoprotective mechanisms. Moreover, depletion of hMø abrogated such effects on the expression of the most highly regulated genes.ConclusionsOur results indicate that AdIGF-I-MSCs are able to induce a pro-fibrotic to resolutive phenotype shift on hepatic macrophages, which is a key early event driving liver fibrosis amelioration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0424-y) contains supplementary material, which is available to authorized users.

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“…Besides, activation of the former also activates IRS-2 and PI3K/Akt pathways, which was enhanced by IGF-1, and which led to M2 polarization. Another M2 inducer (IL-13) could also activate type II IL-4 receptor but it could not upregulate the expression of M2-related markers, such as IL-4 [52]. Finally, protection from sepsis by PMFA was achieved as via inhibition of M1 polarization.…”

Section: Preventive and Therapeutic Strategies Dealing With M1/m2 mentioning

confidence: 99%

Chemopreventive Effects of Phytochemicals and Medicines on M1/M2 Polarized Macrophage Role in Inflammation-Related Diseases

Koh

Yang

Lai

et al. 2018

IJMS

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Macrophages can polarize into two different states (M1 and M2), which play contrasting roles during pathogenesis or tissue damage. M1 polarized macrophages produce pro-inflammatory cytokines and mediators resulting in inflammation, while M2 macrophages have an anti-inflammatory effect. Secretion of appropriate cytokines and chemokines from macrophages can lead to the modification of the microenvironment for bridging innate and adaptive immune responses. Increasing evidence suggests that polarized macrophages are pivotal for disease progression, and the regulation of macrophage polarization may provide a new approach in therapeutic treatment of inflammation-related diseases, including cancer, obesity and metabolic diseases, fibrosis in organs, brain damage and neuron injuries, and colorectal disease. Polarized macrophages affect the microenvironment by secreting cytokines and chemokines while cytokines or mediators that are produced by resident cells or tissues may also influence macrophages behavior. The interplay of macrophages and other cells can affect disease progression, and therefore, understanding the activation of macrophages and the interaction between polarized macrophages and disease progression is imperative prior to taking therapeutic or preventive actions. Manipulation of macrophages can be an entry point for disease improvement, but the mechanism and potential must be understood. In this review, some advanced studies regarding the role of macrophages in different diseases, potential mechanisms involved, and intervention of drugs or phytochemicals, which are effective on macrophage polarization, will be discussed.

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Involvement of IGF-1 and Akt in M1/M2 activation state in bone marrow-derived macrophages

Cited by 51 publications

References 30 publications

NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury

NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury

Involvement of hepatic macrophages in the antifibrotic effect of IGF-I-overexpressing mesenchymal stromal cells

Chemopreventive Effects of Phytochemicals and Medicines on M1/M2 Polarized Macrophage Role in Inflammation-Related Diseases

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