The IL-4/STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p

Zsolt Czimmerer, Tamas Varga, Mate Kiss, Cesaré Ovando Vázquez, Quang Minh Doan-Xuan, Dominik Rückerl, Sudhir Gopal Tattikota, Xin Yan, Zsuzsanna S. Nagy, Bence Daniel, Szilard Poliska, Attila Horvath, Gergely Nagy, E. Várallyay, Matthew N. Poy, Judith E. Allen, Z. Bacsó, Cei Abreu-Goodger, L. Nagy

Research output: Contribution to journalArticle

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Abstract

Background: IL-4-driven alternative macrophage activation and proliferation are characteristic features of both antihelminthic immune responses and wound healing in contrast to classical macrophage activation, which primarily occurs during inflammatory responses. The signaling pathways defining the genome-wide microRNA expression profile as well as the cellular functions controlled by microRNAs during alternative macrophage activation are largely unknown. Hence, in the current work we examined the regulation and function of IL-4-regulated microRNAs in human and mouse alternative macrophage activation. Methods: We utilized microarray-based microRNA profiling to detect the dynamic expression changes during human monocyte-macrophage differentiation and IL-4-mediated alternative macrophage activation. The expression changes and upstream regulatory pathways of selected microRNAs were further investigated in human and mouse in vitro and in vivo models of alternative macrophage activation by integrating small RNA-seq, ChIP-seq, ChIP-quantitative PCR, and gene expression data. MicroRNA-controlled gene networks and corresponding functions were identified using a combination of transcriptomic, bioinformatic, and functional approaches. Results: The IL-4-controlled microRNA expression pattern was identified in models of human and mouse alternative macrophage activation. IL-4-dependent induction of miR-342-3p and repression of miR-99b along with miR-125a-5p occurred in both human and murine macrophages in vitro. In addition, a similar expression pattern was observed in peritoneal macrophages of Brugia malayi nematode-implanted mice in vivo. By using IL4Rα- and STAT6-deficient macrophages, we were able to show that IL-4-dependent regulation of miR-342-3p, miR-99b, and miR-125a-5p is mediated by the IL-4Rα-STAT6 signaling pathway. The combination of gene expression studies and chromatin immunoprecipitation experiments demonstrated that both miR-342-3p and its host gene, EVL, are coregulated directly by STAT6. Finally, we found that miR-342-3p is capable of controlling macrophage survival through targeting an anti-apoptotic gene network including Bcl2l1. Conclusions: Our findings identify a conserved IL-4/STAT6-regulated microRNA signature in alternatively activated human and mouse macrophages. Moreover, our study indicates that miR-342-3p likely plays a pro-apoptotic role in such cells, thereby providing a negative feedback arm to IL-4-dependent macrophage proliferation.

Original languageEnglish
Article number63
JournalGenome Medicine
Volume8
Issue number1
DOIs
Publication statusPublished - May 31 2016

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Macrophage Activation
MicroRNAs
Interleukin-4
Cell Survival
Macrophages
Gene Regulatory Networks
Brugia malayi
Gene Expression
Chromatin Immunoprecipitation
Peritoneal Macrophages
Computational Biology
Wound Healing
Monocytes
Genome
RNA
Polymerase Chain Reaction
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology
  • Molecular Medicine

Cite this

The IL-4/STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p. / Czimmerer, Zsolt; Varga, Tamas; Kiss, Mate; Vázquez, Cesaré Ovando; Doan-Xuan, Quang Minh; Rückerl, Dominik; Tattikota, Sudhir Gopal; Yan, Xin; Nagy, Zsuzsanna S.; Daniel, Bence; Poliska, Szilard; Horvath, Attila; Nagy, Gergely; Várallyay, E.; Poy, Matthew N.; Allen, Judith E.; Bacsó, Z.; Abreu-Goodger, Cei; Nagy, L.

In: Genome Medicine, Vol. 8, No. 1, 63, 31.05.2016.

Research output: Contribution to journalArticle

Czimmerer, Z, Varga, T, Kiss, M, Vázquez, CO, Doan-Xuan, QM, Rückerl, D, Tattikota, SG, Yan, X, Nagy, ZS, Daniel, B, Poliska, S, Horvath, A, Nagy, G, Várallyay, E, Poy, MN, Allen, JE, Bacsó, Z, Abreu-Goodger, C & Nagy, L 2016, 'The IL-4/STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p', Genome Medicine, vol. 8, no. 1, 63. https://doi.org/10.1186/s13073-016-0315-y
Czimmerer, Zsolt ; Varga, Tamas ; Kiss, Mate ; Vázquez, Cesaré Ovando ; Doan-Xuan, Quang Minh ; Rückerl, Dominik ; Tattikota, Sudhir Gopal ; Yan, Xin ; Nagy, Zsuzsanna S. ; Daniel, Bence ; Poliska, Szilard ; Horvath, Attila ; Nagy, Gergely ; Várallyay, E. ; Poy, Matthew N. ; Allen, Judith E. ; Bacsó, Z. ; Abreu-Goodger, Cei ; Nagy, L. / The IL-4/STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p. In: Genome Medicine. 2016 ; Vol. 8, No. 1.
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abstract = "Background: IL-4-driven alternative macrophage activation and proliferation are characteristic features of both antihelminthic immune responses and wound healing in contrast to classical macrophage activation, which primarily occurs during inflammatory responses. The signaling pathways defining the genome-wide microRNA expression profile as well as the cellular functions controlled by microRNAs during alternative macrophage activation are largely unknown. Hence, in the current work we examined the regulation and function of IL-4-regulated microRNAs in human and mouse alternative macrophage activation. Methods: We utilized microarray-based microRNA profiling to detect the dynamic expression changes during human monocyte-macrophage differentiation and IL-4-mediated alternative macrophage activation. The expression changes and upstream regulatory pathways of selected microRNAs were further investigated in human and mouse in vitro and in vivo models of alternative macrophage activation by integrating small RNA-seq, ChIP-seq, ChIP-quantitative PCR, and gene expression data. MicroRNA-controlled gene networks and corresponding functions were identified using a combination of transcriptomic, bioinformatic, and functional approaches. Results: The IL-4-controlled microRNA expression pattern was identified in models of human and mouse alternative macrophage activation. IL-4-dependent induction of miR-342-3p and repression of miR-99b along with miR-125a-5p occurred in both human and murine macrophages in vitro. In addition, a similar expression pattern was observed in peritoneal macrophages of Brugia malayi nematode-implanted mice in vivo. By using IL4Rα- and STAT6-deficient macrophages, we were able to show that IL-4-dependent regulation of miR-342-3p, miR-99b, and miR-125a-5p is mediated by the IL-4Rα-STAT6 signaling pathway. The combination of gene expression studies and chromatin immunoprecipitation experiments demonstrated that both miR-342-3p and its host gene, EVL, are coregulated directly by STAT6. Finally, we found that miR-342-3p is capable of controlling macrophage survival through targeting an anti-apoptotic gene network including Bcl2l1. Conclusions: Our findings identify a conserved IL-4/STAT6-regulated microRNA signature in alternatively activated human and mouse macrophages. Moreover, our study indicates that miR-342-3p likely plays a pro-apoptotic role in such cells, thereby providing a negative feedback arm to IL-4-dependent macrophage proliferation.",
author = "Zsolt Czimmerer and Tamas Varga and Mate Kiss and V{\'a}zquez, {Cesar{\'e} Ovando} and Doan-Xuan, {Quang Minh} and Dominik R{\"u}ckerl and Tattikota, {Sudhir Gopal} and Xin Yan and Nagy, {Zsuzsanna S.} and Bence Daniel and Szilard Poliska and Attila Horvath and Gergely Nagy and E. V{\'a}rallyay and Poy, {Matthew N.} and Allen, {Judith E.} and Z. Bacs{\'o} and Cei Abreu-Goodger and L. Nagy",
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T1 - The IL-4/STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p

AU - Czimmerer, Zsolt

AU - Varga, Tamas

AU - Kiss, Mate

AU - Vázquez, Cesaré Ovando

AU - Doan-Xuan, Quang Minh

AU - Rückerl, Dominik

AU - Tattikota, Sudhir Gopal

AU - Yan, Xin

AU - Nagy, Zsuzsanna S.

AU - Daniel, Bence

AU - Poliska, Szilard

AU - Horvath, Attila

AU - Nagy, Gergely

AU - Várallyay, E.

AU - Poy, Matthew N.

AU - Allen, Judith E.

AU - Bacsó, Z.

AU - Abreu-Goodger, Cei

AU - Nagy, L.

PY - 2016/5/31

Y1 - 2016/5/31

N2 - Background: IL-4-driven alternative macrophage activation and proliferation are characteristic features of both antihelminthic immune responses and wound healing in contrast to classical macrophage activation, which primarily occurs during inflammatory responses. The signaling pathways defining the genome-wide microRNA expression profile as well as the cellular functions controlled by microRNAs during alternative macrophage activation are largely unknown. Hence, in the current work we examined the regulation and function of IL-4-regulated microRNAs in human and mouse alternative macrophage activation. Methods: We utilized microarray-based microRNA profiling to detect the dynamic expression changes during human monocyte-macrophage differentiation and IL-4-mediated alternative macrophage activation. The expression changes and upstream regulatory pathways of selected microRNAs were further investigated in human and mouse in vitro and in vivo models of alternative macrophage activation by integrating small RNA-seq, ChIP-seq, ChIP-quantitative PCR, and gene expression data. MicroRNA-controlled gene networks and corresponding functions were identified using a combination of transcriptomic, bioinformatic, and functional approaches. Results: The IL-4-controlled microRNA expression pattern was identified in models of human and mouse alternative macrophage activation. IL-4-dependent induction of miR-342-3p and repression of miR-99b along with miR-125a-5p occurred in both human and murine macrophages in vitro. In addition, a similar expression pattern was observed in peritoneal macrophages of Brugia malayi nematode-implanted mice in vivo. By using IL4Rα- and STAT6-deficient macrophages, we were able to show that IL-4-dependent regulation of miR-342-3p, miR-99b, and miR-125a-5p is mediated by the IL-4Rα-STAT6 signaling pathway. The combination of gene expression studies and chromatin immunoprecipitation experiments demonstrated that both miR-342-3p and its host gene, EVL, are coregulated directly by STAT6. Finally, we found that miR-342-3p is capable of controlling macrophage survival through targeting an anti-apoptotic gene network including Bcl2l1. Conclusions: Our findings identify a conserved IL-4/STAT6-regulated microRNA signature in alternatively activated human and mouse macrophages. Moreover, our study indicates that miR-342-3p likely plays a pro-apoptotic role in such cells, thereby providing a negative feedback arm to IL-4-dependent macrophage proliferation.

AB - Background: IL-4-driven alternative macrophage activation and proliferation are characteristic features of both antihelminthic immune responses and wound healing in contrast to classical macrophage activation, which primarily occurs during inflammatory responses. The signaling pathways defining the genome-wide microRNA expression profile as well as the cellular functions controlled by microRNAs during alternative macrophage activation are largely unknown. Hence, in the current work we examined the regulation and function of IL-4-regulated microRNAs in human and mouse alternative macrophage activation. Methods: We utilized microarray-based microRNA profiling to detect the dynamic expression changes during human monocyte-macrophage differentiation and IL-4-mediated alternative macrophage activation. The expression changes and upstream regulatory pathways of selected microRNAs were further investigated in human and mouse in vitro and in vivo models of alternative macrophage activation by integrating small RNA-seq, ChIP-seq, ChIP-quantitative PCR, and gene expression data. MicroRNA-controlled gene networks and corresponding functions were identified using a combination of transcriptomic, bioinformatic, and functional approaches. Results: The IL-4-controlled microRNA expression pattern was identified in models of human and mouse alternative macrophage activation. IL-4-dependent induction of miR-342-3p and repression of miR-99b along with miR-125a-5p occurred in both human and murine macrophages in vitro. In addition, a similar expression pattern was observed in peritoneal macrophages of Brugia malayi nematode-implanted mice in vivo. By using IL4Rα- and STAT6-deficient macrophages, we were able to show that IL-4-dependent regulation of miR-342-3p, miR-99b, and miR-125a-5p is mediated by the IL-4Rα-STAT6 signaling pathway. The combination of gene expression studies and chromatin immunoprecipitation experiments demonstrated that both miR-342-3p and its host gene, EVL, are coregulated directly by STAT6. Finally, we found that miR-342-3p is capable of controlling macrophage survival through targeting an anti-apoptotic gene network including Bcl2l1. Conclusions: Our findings identify a conserved IL-4/STAT6-regulated microRNA signature in alternatively activated human and mouse macrophages. Moreover, our study indicates that miR-342-3p likely plays a pro-apoptotic role in such cells, thereby providing a negative feedback arm to IL-4-dependent macrophage proliferation.

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