The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages

Czimmerer, Zsolt; Dániel, Bence; Horváth, Attila; Rückerl, Dominik; Nagy, Gergely; Kiss, Máté; Peloquin, Matthew; Budai, Marietta Margit; Cuaranta-Monroy, Ixchelt; Simándi, Zoltán; Steiner, László; Nagy, Béla; Póliska, Szilárd; Bankó, Csaba; Bacsó, Zsolt; Schulman, Ira G.; Sauer, Sascha; Deleuze, Jean; Allen, Judith E.; Benkő, Szilvia; Nagy, László

doi:10.1016/j.immuni.2017.12.010

Cited by 185 publications

(211 citation statements)

References 49 publications

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“…In other words, RACK1 could inhibit the expression of IL‐6, CCL5 and CSF in OSCC cells and their secretion and then inhibit macrophage recruitment to the TME of OSCC. Furthermore, during the polarization process of macrophages, AP‐1, NF‐κB and STAT1 activation is required for M1 polarization, and mTOR, PPARγ/δ and STAT6 activation is critical for M2 polarization (Czimmerer et al , ; Zhu et al , ). Our study demonstrated that both M1 and M2 key activation factors, such as AP‐1, NF‐κB, STAT1 mTOR, and PPARγ, were significantly increased after RACK1 was silenced in OSCC cells.…”

Section: Discussionmentioning

confidence: 99%

RACK1 promotes cancer progression by increasing the M2/M1 macrophage ratio via the NF‐κB pathway in oral squamous cell carcinoma

et al. 2020

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Receptor for activated C kinase 1 (RACK1) has been shown to promote oral squamous cell carcinoma (OSCC) progression, and RACK1 expression levels have been negatively correlated with prognosis in patients with OSCC. Here, we investigated the impact of RACK1 OSCC expression on the recruitment and differentiation of tumor‐associated macrophages. High RACK1 expression in OSCC cells correlated with increased M2 macrophage infiltration in tumor samples from a clinical cohort study. Moreover, the combination of RACK1 expression and the M2/M1 ratio could successfully predict prognosis in OSCC. OSCC cells with high RACK1 expression inhibited the migration of THP‐1 cells, promoted M2‐like macrophage polarization in vitro, and increased the proportion of M2‐like macrophages in a xenograft mouse model. Moreover, both M1‐ and M2‐like macrophage polarization‐associated proteins were induced in macrophages cocultured with RACK1‐silenced cell supernatant. A mechanistic study revealed that the expression and secretion of C‐C motif chemokine 2 (CCL2), C‐C motif chemokine 5 (CCL5), interleukin‐6 (IL‐6), and interleukin‐1 (IL‐1) are closely related to RACK1 expression. In addition, blocking nuclear factor‐kappa B (NF‐κB) could promote M2‐like macrophage polarization. These results indicate that RACK1 and the M2/M1 ratio are predictors of a poor prognosis in OSCC. RACK1 promotes M2‐like polarization by regulating NF‐κB and could be used as a potential therapeutic target for antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

RACK1 promotes cancer progression by increasing the M2/M1 macrophage ratio via the NF‐κB pathway in oral squamous cell carcinoma

et al. 2020

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“…In this study that GPS2 depletion did not influence IL-4/ STAT6-dependent repression of Abca1, further supporting the LPS/p65 selectivity of the GPS2/ABCA1 pathway. However, given the genomic colocalization of STAT6 and GPS2 at many IL-4-regulated gene loci, the potential interplay of these 2 factors remain to be explored (36,38). Of interest is further that depletion of HDAC3 in RAW cells reduced Abca1 expression, the opposite of what would be expected if HDAC3 solely functions as a key component of the corepressor complex.…”

Section: Discussionmentioning

confidence: 99%

“…To further investigate the role of GPS2 in modulating signal-dependent Abca1 expression in macrophages, we examined IL-4/STAT6 signaling linked to alternative M2 macrophage activation, as it was reported to inhibit Abca1 expression in mouse macrophages (38). ChIP-seq analysis from published BMDM datasets suggests colocalization of GPS2 with the major IL-4-induced TF STAT-6 at both the Abca1 promoter and enhancer (Supplemental Fig.…”

Section: Lxr Activation Of Abca1 Does Not Require Gps2 But Lxr Transmentioning

confidence: 99%

G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages

et al. 2018

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Macrophages play important roles in linking alterations of cholesterol metabolism and inflammation to the development of atherosclerosis. Previous studies have identified several positive and negative crosstalk mechanisms that connect cholesterol efflux and inflammation at the transcriptional level. Of particular relevance is that the expression of ATP‐binding cassette transporter A1 (Abca1), a main regulator of cholesterol efflux, can be induced by oxysterol receptor LXR agonists but also by bacterial endotoxins, such as LPS, that activate TLR4 signaling. However, the extent to which these pathways influence each other has remained incompletely understood. We investigated the possible role of the transcriptional coregulator G protein pathway suppressor 2 (GPS2) in LPS‐induced Abca1 expression and cholesterol efflux in mouse and human macrophages. To activate Abca1, GPS2 cooperates with the LPS‐inducible NF‐κB subunit p65, but not with LXRs nor with corepressor complex subunits that otherwise cooperate with GPS2 to repress proinflammatory gene expression. Overall, our work identifies a regulatory chromatin component of crosstalk mechanisms between cholesterol efflux and inflammation that specifically affects ABCA1. Because GPS2 expression is down‐regulated in some humans with obese and type 2 diabetes, the macrophage GPS‐2/ABC‐A1 pathway could be altered and contribute to atherogenesis.—Huang, Z., Liang, N., Damdimopoulos, A., Fan, R., Treuter, E. G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages. FASEB J. 33, 1631–1643 (2019). http://www.fasebj.org

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“…There is extensive crosstalk in the polarization programs in populations of macrophages presented with opposing cues 14,15 ; however, the complexity of macrophage polarization has not yet been explored at single-cell resolution. Such single-cell measurements are important because macrophage populations display significant cell-to-cell heterogeneity in their responses even following acute stimulation with LPS 16–18 .…”

Section: Introductionmentioning

confidence: 99%

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

Muñoz-Rojas

Kelsey

Pappalardo

et al. 2020

Preprint

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14Macrophages are innate immune cells that contribute to fighting infections, tissue repair, and 15 maintaining tissue homeostasis. To enable such functional diversity, macrophages resolve 16 potentially conflicting cues in the microenvironment via mechanisms that remain unclear. Here, 17we used single-cell RNA sequencing to explore how individual macrophages respond when co-18 stimulated with the inflammatory stimuli, LPS+IFN-γ, and the resolving cytokine, IL-4. We found 19 that co-stimulated macrophages displayed a distinct global transcriptional program. However, 20 variable negative cross-regulation between some LPS+IFN-γ-and IL-4-specific genes resulted in 21 significant cell-to-cell heterogeneity in transcription. Interestingly, negative cross-regulation led 22to mutually exclusive expression of the T-cell-polarizing cytokines Il6 and Il12b versus the IL-4-23 associated factors Arg1 and Chil3 in single co-stimulated macrophages, and single-cell secretion 24 measurements showed that these specialized functions were maintained for at least 48 hours. 25Overall, our study suggests that increasing functional diversity in the population is one strategy 26 macrophages use to respond to conflicting environmental cues. 27 LPS+IFN-γ or the IL-4 transcriptional program in response to co-stimulation. 131 132 Co-stimulation with LPS+IFN-γ and IL-4 induces transcriptional cross-regulation that 133 varies substantially across individual cells 134We next focused on how co-stimulation with LPS+IFN-γ and IL-4 affected the expression 135 of genes uniquely upregulated by either LPS+IFN-γ or IL-4 alone ( Fig. 2a), which we refer to as 136 the core gene programs. For both LPS+IFN-γ-and IL-4-induced genes, co-stimulation with the 137 other cue caused both transcriptional upregulation and inhibition in a subset of core genes 138 belonging to each program, consistent with our own and previously reported observations 14 . 139Among the LPS+IFN-γ-induced core genes, 87 were inhibited by co-stimulation and 97 were 140 augmented by co-stimulation, while among the IL-4-induced core genes, 196 were inhibited and 141 16 were augmented by co-stimulation (Fig. 2b). 142We compared observations from our single-cell dataset to population-level RT-qPCR data 514

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The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages

Cited by 185 publications

References 49 publications

RACK1 promotes cancer progression by increasing the M2/M1 macrophage ratio via the NF‐κB pathway in oral squamous cell carcinoma

RACK1 promotes cancer progression by increasing the M2/M1 macrophage ratio via the NF‐κB pathway in oral squamous cell carcinoma

G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

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