CREB pathway links PGE2 signaling with macrophage polarization

Luan, Bing; Yoon, Young-Sil; Lay, John Le; Kaestner, Klaus H.; Hedrick, Susan; Montminy, Marc

doi:10.1073/pnas.1519644112

Cited by 244 publications

(198 citation statements)

References 27 publications

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“…These results are consistent with the widely accepted notion that PGE2 skews macrophages toward M2-type macrophages that promote tumor growth in the tumor microenvironment (32). The results also support the scenario that PGE2 release under hypoxic conditions in vivo is a newly identified mechanism of tumor immune evasion, wherein dying tumor cells assist the growth of surviving tumor cells by modifying the tumor microenvironment.…”

Section: Resultssupporting

confidence: 91%

PGE2 induced in and released by dying cells functions as an inhibitory DAMP

Hangai

Kimura

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

135

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Cellular components released into the external milieu as a result of cell death and sensed by the body are generally termed damage-associated molecular patterns (DAMPs). Although DAMPs are conventionally thought to be protective to the host by evoking inflammatory responses important for immunity and wound repair, there is the prevailing notion that dysregulated release of DAMPs can also underlie or exacerbate disease development. However, the critical issue for how resultant DAMP-mediated responses are regulated has heretofore not been fully addressed. In the present study, we identify prostaglandin E2 (PGE2) as a DAMP that negatively regulates immune responses. We show that the production of PGE2 is augmented under cell death-inducing conditions via the transcriptional induction of the cyclooxygenase 2 (COX2) gene and that cell-released PGE2 suppresses the expression of genes associated with inflammation, thereby limiting the cell’s immunostimulatory activities. Consistent with this, inhibition of the PGE2 synthesis pathway potentiates the inflammation induced by dying cells. We also provide in vivo evidence for a protective role of PGE2 released upon acetaminophen-induced liver injury as well as a pathogenic role for PGE2 during tumor cell growth. Our study places this classically known lipid mediator in an unprecedented context—that is, an inhibitory DAMP vis-à-vis activating DAMPs, which may have translational implications for designing more effective therapeutic regimens for inflammation-associated diseases.

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Section: Resultssupporting

confidence: 91%

PGE2 induced in and released by dying cells functions as an inhibitory DAMP

Hangai

Kimura

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

135

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“…6,20 Our previous work showed that CREB induces the M2 polarization of macrophages, an anti-inflammatory phenotype, via the induction of KLF4. 12 In the present work, we describe a previously unrecognized negative feedback mechanism for the regulation of NF-κB by TLR ligands via CREB-induced ICER. In this mechanism, ICER expression is upregulated by TLR ligands via p38-mediated CREB activation, and ICER, in turn, inhibits NF-κB transcriptional activity by interaction with the NF-κB p65 subunit.…”

Section: Discussionmentioning

confidence: 81%

“…We further evaluated the role of CREB in LPS-induced ICER expression by expressing the dominant-negative CREB inhibitor ACREB, a synthetic polypeptide that selectively heterodimerizes with, and disrupts, the DNA-binding activity of all CREB family members (CREB1, CREM, and ATF1) in WT PMs. 12 Similar to knocking out CREB in PMs, ACREB expression disrupted LPS-induced ICER gene expression (Figure 1g). Exposure to LPS consistently increased phospho-CREB occupancy over the ICER promoter in PMs (Figure 1h) and this effect was inhibited by SB203580 or SB202190 (Figure 1i).…”

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confidence: 86%

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A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses

Qiu

et al. 2016

Cell Death Differ

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The NF-κB pathway has important roles in innate immune responses and its regulation is critical to maintain immune homeostasis. Here, we report a newly discovered feedback mechanism for the regulation of this pathway by TLR ligands in macrophages. Lipopolysaccharide (LPS) induced the expression of ICER via p38-mediated activation of CREB in macrophages. ICER, in turn, inhibited the transcriptional activity of NF-κB by direct interaction with the p65 subunit of NF-κB. Deficiency in ICER elevated binding of NF-κB to promoters of pro-inflammatory genes and their subsequent gene expression. Mice deficient in ICER were hypersensitive to LPS-induced endotoxic shock and showed propagated inflammation. Whereas ICER expression in ICER KO bone marrow transplanted mice rescued the ultra-inflammation phenotype, expression of a p65 binding-deficient ICER mutant failed to do so. Our results thus establish p38-CREB-ICER as key components of a negative feedback mechanism necessary to regulate TLR-driven inflammation. Cell Death and Differentiation (2017) 24, 492-499; doi:10.1038/cdd.2016; published online 23 December 2016Activation of TLR4, a pattern recognition receptor used in the innate immune system, by lipopolysaccharide (LPS) leads to the transcription of pro-inflammatory mediators that promote innate immune responses.1 One critical pathway triggered by TLR4 is the NF-κB pathway.2 TLR4 initiates a signaling cascade through adapter molecules MyD88 and TRIF, resulting in TRAF6 activation. TRAF6 in turn triggers the phosphorylation of IκB by IKK and proteosomal degradation of IκB. Subsequently, NF-κB disassociates from IκB and translocates to the nucleus where it promotes the transcription of genes involved in pro-inflammatory responses.3,4 Activation of TRAF6 also leads to downstream activation of the MAPK cascade, including JNKs and p38 isoforms. 5 The p38 pathway has attracted considerable interest as a possible target for antiinflammatory drugs. Activation of p38 results in the activation of CREB, a transcription factor that regulates diverse cellular responses including proliferation, survival and immune responses. CREB is phosphorylated and activated by MSK1/2, a downstream kinase of p38, and subsequently mediates the transcription of genes containing a cAMP-responsive element. Several anti-inflammatory genes possess this cAMPresponsive element, including Dusp1 and IL-10. 6 In addition, phosphorylated CREB has been proposed to directly inhibit NF-κB activation by blocking the binding of CREB binding protein to the NF-κB complex, thereby limiting proinflammatory responses. 7Inducible cAMP early repressors (ICERs) are members of the cAMP-response element (CRE) modulator family and are induced by CREB.8 ICER is transcribed via an alternative internal promoter in the CREM gene and consists of four different isoforms generated by alternative splicing of its transcript (ICERI, ICERIγ, ICERII, ICERIIγ). 9 The isoforms encode either CREB-like (ICERI) or CREM-like (ICERII) DNA-binding domains (DBDs) with or without the alternat...

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“…For mouse peritoneal Mfs, EpETrEs (particularly 11,12-EpETrE) regulated polarization by attenuating NF-kB via activation of peroxisome proliferator-activated receptor-a/g and heme oxygenase 1 (52). Via cAMP/cAMP response element binding protein, PGE 2 enhanced M2 polarization of mouse bone marrow-derived Mfs (53). PGE 2 also induced IL-10-producing Mfs in vitro and reduced allergic lung inflammation in mice (54).…”

Section: Discussionmentioning

confidence: 99%

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

et al. 2017

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M1 and M2 activated macrophages (Mfs) have different roles in inflammation. Because pathogens may first encounter resting cells, we investigated lipid mediator profiles prior to full activation. Human monocytes were differentiated with granulocyte Mf colony-stimulating factor (GM-CSF) or Mf colony-stimulating factor (M-CSF), which are known to prime toward M1 or M2 phenotypes, respectively. Lipid mediators released during resting conditions and produced in response to bacterial stimuli (LPS/N-formylmethionyl-leucyl-phenylalanine or peptidoglycan) were quantified by liquid chromatography-mass spectrometry. In resting conditions, both Mf phenotypes released primarily proresolving lipid mediators (prostaglandin E 2 metabolite, lipoxin A 4 , and 18-hydroxyeicosapentaenoic acid). A striking shift toward proinflammatory eicosanoids was observed when the same cells were exposed (30 min) to bacterial stimuli: M-CSF Mfs produced considerably more 5-lipoxygenase products, particularly leukotriene C 4 , potentially linked to M2 functions in asthma. Prostaglandins were formed by both Mf types. In the M-CSF cells, there was also an enhanced release of arachidonic acid and activation of cytosolic phospholipase A 2 . However, GM-CSF cells expressed higher levels of 5-lipoxygenase and 5-lipoxygenase-activating protein, and in ionophore incubations these cells also produced the highest levels of 5-hydroxyeicosatetraenoic acid. In summary, GM-CSF and M-CSF Mfs displayed similar proresolving lipid mediator formation in resting conditions but shifted toward different proinflammatory eicosanoids upon bacterial stimuli. This demonstrates that preference for specific eicosanoid pathways is primed by CSFs before full M1/M2 activation.-Lukic, A., Larssen, P., Fauland, A., Samuelsson, B., Wheelock, C. E., Gabrielsson, S., Radmark, O. GM-CSF-and M-CSF-primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures. FASEB J. 31, 4370-4381 (2017). www.fasebj.orgMacrophages (Mfs) orchestrate the inflammatory process from early onset to the resolution phase (1, 2). A major issue in Mf biology is to characterize functional phenotypes, currently described as a heterogeneous spectrum of activated states, from M1 to M2 (3, 4). Stimulating factors, such as cytokines and pathogens, can induce specific phenotypes: originally IFN-g + LPS activation resulted in a proinflammatory M1 state, whereas IL-4 activation induced the alternatively activated M2 state. Polarized cells express distinct markers, such as transcription factors, cytokines, and surface markers; these are the main tools to define Mf phenotypes. A number of transcripts have been reported to differ between M1 and M2 Mfs, including mRNAs for enzymes involved in eicosanoid metabolism (5).Eicosanoids originate from arachidonic acid (AA), released from membrane phospholipids by phospholipases, typically cytosolic phospholipase A 2 (cPLA 2 ) (6). Free AA is further metabolized via 3 enzymatic pathways: lipoxygenase (LO), cyclooxygenase (COX), and cyto...

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CREB pathway links PGE2 signaling with macrophage polarization

Cited by 244 publications

References 27 publications

PGE2 induced in and released by dying cells functions as an inhibitory DAMP

PGE2 induced in and released by dying cells functions as an inhibitory DAMP

A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

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