Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function

Whyte, Claire S.; Bishop, Eileen; Rückerl, Dominik; Gaspar-Pereira, Silvia; Barker, Robert N.; Allen, Judith E.; Rees, Andrew J.; Wilson, Heather M.

doi:10.1189/jlb.1110644

Cited by 184 publications

(195 citation statements)

References 49 publications

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“…STAT-mediated activation of macrophages is regulated by members of the SOCS family. IL-4 and IFN-γ, the latter in concert with TLR stimulation, upregulate SOCS1 and SOCS3, which in turn inhibit the action of STAT1 and STAT3, respectively (17,18).…”

Section: Molecular Determinants Of Macrophage Polarizationmentioning

confidence: 99%

Macrophage plasticity and polarization: in vivo veritas

2012

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(Retnla, Fizz1), and chitinase 3-like 3 (Chi3l3, Ym1) (14). IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype (4,15,16). STAT-mediated activation of macrophages is regulated by members of the SOCS family. IL-4 and IFN-γ, the latter in concert with TLR stimulation, upregulate SOCS1 and SOCS3, which in turn inhibit the action of STAT1 and STAT3, respectively (17,18).Downstream of, or in parallel with, the IRF/STAT/SOCS pathway, a panel of transcription factors orchestrates polarized macrophage activation. The nuclear receptors PPARγ (19) and PPARδ (20,21) control distinct subsets of genes associated with M2 macrophage activation and oxidative metabolism (Figure 1). Interestingly, STAT6 coordinates and synergizes with both PPARγ (22) and Krüppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function (23, 24). KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPARγ) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-κB activation. KLF2 regulates macrophage activation by inhibiting NF-κB/ HIF-1α activities (25). IL-4 also induces c-Myc activity in human macrophages (26), which controls genes of M2 activation (Scarb1, Alox15, and Mrc1) as well as STAT6 and PPARγ activation (26).TLR engagement leads to NF-κB activation and production of inflammatory mediators (27) associated with M1 macrophages. However, NF-κB activation also activates a genetic program essential for resolution of inflammation (28) and for M2 polarization of tumor-associated macrophages (TAMs) (29). Moreover, induction of p50 NF-κB homodimers is essential for M2 polarization in vitro and in vivo (30). The hypoxia-inducible factors HIF-1α and HIF-2α are expressed differentially in M1- and M2-polarized macrophages (31) and regulate inducible NOS2 (M1) and arginase 1 (M2), respectively. Figure 1Mechanisms of macrophage polarization. The major pathways of macrophage polarization are outlined. The crosstalk between the M1-M2 macrophage-polarizing pathways is also indicated. The balance between activation of STAT1 and STAT3/STAT6 finely regulates macrophage polarization and activity. A predominance of NF-κB and STAT1 activation promotes M1 macrophage polarization, resulting in cytotoxic and inflammatory functions. In contrast, a predominance of STAT3 and STAT6 activation results in M2 macrophage polarization, associated with immune suppression and tumor progression. PPARγ and PPARδ control distinct aspects of M2 macrophage activation and oxidative metabolism. KLF4 and KLF2 participate in the promotion of M2 macrophage functions by cooperating with STAT6 and suppressing the NF-κB/HIF-1α-dependent transcription, respectively. IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing Jmjd3-IRF4 axis to inhibit IRF5-mediated M1 polarization. IL-10 promotes M2 polarization through the induction of p50 NF-κB homodimer, c-Maf, and STAT3 activities. Epigenetic ...

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Section: Molecular Determinants Of Macrophage Polarizationmentioning

confidence: 99%

Macrophage plasticity and polarization: in vivo veritas

2012

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“…3A). Similarly, emodin inhibited the IL4 induced expression of the canonical M2 genes Arg1, Mrc1, and Ch3l3 (7.69-, 2.29-, and 4.24-fold reduction, respectively) and the transcription factors SOCS1 and IRF4 (22.9-and 97.43-fold reduction, respectively), which have both shown to be necessary for M2 activation (8,37,38) (Fig. 3B).…”

Section: Emodin Affects the Activation Of Different Transcriptionalmentioning

confidence: 99%

Emodin Bidirectionally Modulates Macrophage Polarization and Epigenetically Regulates Macrophage Memory

Iwanowycz

Wang

Altomare

et al. 2016

Journal of Biological Chemistry

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Macrophages are pleiotropic cells capable of performing a broad spectrum of functions. Macrophage phenotypes are classified along a continuum between the extremes of proinflammatory M1 macrophages and anti-inflammatory M2 macrophages. The seemingly opposing functions of M1 and M2 macrophages must be tightly regulated for an effective and proper response to foreign molecules or damaged tissue. Excessive activation of either M1 or M2 macrophages contributes to the pathology of many diseases. Emodin is a Chinese herb-derived compound and has shown potential to inhibit inflammation in various settings. In this study, we tested the ability of emodin to modulate the macrophage response to both M1 and M2 stimuli. Primary mouse macrophages were stimulated with LPS/IFN␥ or IL4 with or without emodin, and the effects of emodin on gene transcription, cell signaling pathways, and histone modifications were examined by a variety of approaches, including microarray, quantitative real-time PCR, Western blotting, chromatin immunoprecipitation, and functional assays. We found that emodin bidirectionally tunes the induction of LPS/IFN␥-and IL4-responsive genes through inhibiting NFB/IRF5/STAT1 signaling and IRF4/STAT6 signaling, respectively. Thereby, emodin modulates macrophage phagocytosis, migration, and NO production. Furthermore, emodin inhibited the removal of H3K27 trimethylation (H3K27m3) marks and the addition of H3K27 acetylation (H3K27ac) marks on genes required for M1 or M2 polarization of macrophages. In conclusion, our data suggest that emodin is uniquely able to suppress the excessive response of macrophages to both M1 and M2 stimuli and therefore has the potential to restore macrophage homeostasis in various pathologies.

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“…However, the signaling pathways involved in M2 M⌽ function in kidney disease remain unclear. In nonrenal diseases, other signaling pathways have been reported to be important in control of M1 and M2 phenotypes, including, among others, those of C/EBP␤, PPAR␥, IRF family, and STAT family, but as yet they have not been studied in kidney diseases (21,46,71,75,90,96). Several novel signaling molecules, including, among others, ATF3, Kif4, and HIF-1␣, were found by our group to be highly expressed in M1, M2a, or M2c M⌽, respectively (Wang C, Cao Q, Lee VW, Zheng G, Alexander SI, Harris DC, and Wang Y., unpublished observations).…”

Section: Frontiers Of Kidney Macrophage Researchmentioning

confidence: 99%

Pathogenic and protective role of macrophages in kidney disease

Cao

Wang

Harris

2013

American Journal of Physiology-Renal Physiology

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Macrophages (MΦ) are located throughout kidney tissue, where they play important roles in homeostasis, surveillance, tolerance, and cytoprotection. MΦ are highly heterogeneous cells and exhibit distinct phenotypic and functional characteristics depending on their microenvironment and the disease type and stage. Recent studies have identified a dual role for MΦ in several murine models of kidney disease. In this review, we discuss the pathogenic and protective roles of the various MΦ subsets in experimental and human kidney diseases and summarize current progress toward the therapeutic use of MΦ in kidney diseases.

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Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function

Cited by 184 publications

References 49 publications

Macrophage plasticity and polarization: in vivo veritas

Macrophage plasticity and polarization: in vivo veritas

Emodin Bidirectionally Modulates Macrophage Polarization and Epigenetically Regulates Macrophage Memory

Pathogenic and protective role of macrophages in kidney disease

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