An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

Miyamoto, Hiroaki; Katsuyama, Eri; Miyauchi, Yoshiteru; Hoshi, Hiroko; Miyamoto, Kana; Sato, Yuiko; Kobayashi, Tami; Iwasaki, Ryuichiro; Yoshida, Shigeyuki; Mori, Tomoaki; Kanagawa, Hiroya; Fujie, Atsuhiro; Wu, Hao; Morioka, Hideo; Matsumoto, Morio; Toyama, Yoshiaki; Miyamoto, Takeshi

doi:10.1074/jbc.m112.358226

Cited by 35 publications

(30 citation statements)

References 31 publications

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“…Despite being known for diverse biological roles, a role for the JAK/STAT pathway has rarely been reported in relation to cell fusion. Giant cell formation in response to foreign bodies, such as implants, is mediated by activation of fusion-promoting STAT6, which suppresses fusion-inhibitory STAT1, resulting in derepression of the transcription of downstream target genes (Miyamoto et al, 2012). Our findings show an intriguing similarity to these data, and may aid in elucidation of the mechanism underlying macrophage fusion.…”

Section: Discussionsupporting

confidence: 65%

Spatiotemporal regulation of cell fusion by JNK and JAK/STAT signaling during Drosophila wound healing

Lee¹,

Lee²,

Park³

et al. 2017

Development

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Cell-cell fusion is widely observed during development and disease, and imposes a dramatic change on participating cells. Cell fusion should be tightly controlled, but the underlying mechanism is poorly understood. Here, we found that the JAK/STAT pathway suppressed cell fusion during wound healing in the Drosophila larval epidermis, restricting cell fusion to the vicinity of the wound. In the absence of JAK/STAT signaling, a large syncytium containing a 3-fold higher number of nuclei than observed in wild-type tissue formed in wounded epidermis. The JAK/STAT ligand-encoding genes upd2 and upd3 were transcriptionally induced by wounding, and were required for suppressing excess cell fusion. JNK (also known as Basket in flies) was activated in the wound vicinity and activity peaked at ∼8 h after injury, whereas JAK/STAT signaling was activated in an adjoining concentric ring and activity peaked at a later stage. Cell fusion occurred primarily in the wound vicinity, where JAK/STAT activation was suppressed by fusion-inducing JNK signaling. JAK/ STAT signaling was both necessary and sufficient for the induction of βPS integrin (also known as Myospheroid) expression, suggesting that the suppression of cell fusion was mediated at least in part by integrin protein.

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Section: Discussionsupporting

confidence: 65%

Spatiotemporal regulation of cell fusion by JNK and JAK/STAT signaling during Drosophila wound healing

Lee¹,

Lee²,

Park³

et al. 2017

Development

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“…Thus, HDL simultaneously inhibits the basal and IFNγ-induced expression (often STAT1-dependent [36]) of M1 markers, such as iNOS, IL-6 and TNFα. Antagonism between the STAT1 and STAT3 pathways is well described, notably in cardiovascular diseases [37], but reciprocal regulation between STAT1 and STAT6 is an emerging field [38], and our results may be reflecting such a phenomenon mediated by HDL with regard to macrophage inflammatory state.…”

Section: Discussionmentioning

confidence: 58%

HDL Induces the Expression of the M2 Macrophage Markers Arginase 1 and Fizz-1 in a STAT6-Dependent Process

2013

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Our lab has previously shown in a mouse model that normalization of a low HDL level achieves atherosclerotic plaque regression. This included the shift from a pro (“M1”) to an anti-inflammatory (“M2”) phenotypic state of plaque macrophages. Whether HDL can directly cause this phenotypic change and, if so, what the signaling mechanism is, were explored in the present studies. Murine primary macrophages treated with HDL showed increased gene expression for the M2 markers Arginase-1 (Arg-1) and Fizz-1, which are classically induced by IL-4. HDL was able to potentiate the IL-4-induced changes in Arg-1, and tended to do the same for Fizz-1, while suppressing the expression of inflammatory genes in response to IFNγ. The effects of either IL-4 or HDL were suppressed when macrophages were from STAT6-/- mice, but inhibitor studies suggested differential utilization of JAK isoforms by IL-4 and HDL to activate STAT6 by phosphorylation. Overall, our results describe a new function of HDL, namely its ability to directly enrich macrophages in markers of the M2, anti-inflammatory, state in a process requiring STAT6.

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“…Proteins were detected using the following antibodies: anti-phospho-Smad2 (3101, Cell Signaling); anti-phospho-Smad3 (9520, Cell Signaling); anti-Smad2/3 (3102, Cell Signaling); anti-phospho-Smad1/5/8 (9511, Cell Signaling); anti-Smad1 (6944, Cell Signaling); anti-phospho-IGF1 receptor (3024, Cell Signaling); anti-IGF1 receptor (9750, Cell Signaling); anti-Akt (9272, Cell Signaling); anti-phospho Akt (4051, Cell Signaling); and anti-Actin (A2066, Sigma). Bands were quantified by National Institutes of Health imaging, as described (29,30). For in vitro cell culture, C2C12 cells were cultured in growth medium (DMEM supplemented with 10% FCS, penicillin (50 units/ml), and streptomycin (100 g/ml)) and maintained at 37°C in humidified 5% CO 2 atmosphere.…”

Section: Methodsmentioning

confidence: 99%

Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy

Tando¹,

Hirayama

Furukawa³

et al. 2016

Journal of Biological Chemistry

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Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes.

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An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

Cited by 35 publications

References 31 publications

Spatiotemporal regulation of cell fusion by JNK and JAK/STAT signaling during Drosophila wound healing

Spatiotemporal regulation of cell fusion by JNK and JAK/STAT signaling during Drosophila wound healing

HDL Induces the Expression of the M2 Macrophage Markers Arginase 1 and Fizz-1 in a STAT6-Dependent Process

Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy

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