Apolipoprotein e induces antiinflammatory phenotype in macrophages

Daniel Baitsch, Hans H. Bock, Thomas Engel, Ralph Telgmann, Carsten Müller-Tidow, Georg Varga, Martine Bot, Joachim Herz, Horst Robenek, Arnold Von Eckardstein, Jerzy Roch Nofer

Research output: Contribution to journalArticle

142 Citations (Scopus)

Abstract

Objective- Apolipoprotein E (apoE) exerts potent antiinflammatory effects. Here, we investigated the effect of apoE on the functional phenotype of macrophages. Methods and Results- Human apoE receptors very-low-density lipoprotein receptor (VLDL-R) and apoE receptor-2 (apoER2) were stably expressed in RAW264.7 mouse macrophages. In these cells, apoE downregulated markers of the proinflammatory M1 phenotype (inducible nitric oxide synthase, interleukin [IL]-12, macrophage inflammatory protein-1α) but upregulated markers of the antiinflammatory M2 phenotype (arginase I, SOCS3, IL-1 receptor antagonist [IL-1RA]). In addition, M1 macrophage responses (migration, generation of reactive oxygen species, antibody-dependent cell cytotoxicity, phagocytosis), as well as poly(I:C)- or interferon-γ-induced production of proinflammatory cytokines; cyclooxygenase-2 expression; and activation of nuclear factor-κB, IκB, and STAT1, were suppressed in VLDL-R- or apoER2-expressing cells. Conversely, the suppression of the M2 phenotype and the enhanced response to poly(I:C) were observed in apoE-producing bone marrow macrophages derived from VLDL-R-deficient mice but not wild-type or low-density lipoprotein receptor-deficient mice. The modulatory effects of apoE on macrophage polarization were inhibited in apoE receptor-expressing RAW264.7 cells exposed to SB220025, a p38 mitogen-activated protein kinase inhibitor, and PP1, a tyrosine kinase inhibitor. Accordingly, apoE induced tyrosine kinase-dependent activation of p38 mitogen-activated protein kinase in VLDL-R- or apoER2-expressing macrophages. Under in vivo conditions, apoE mice transplanted with apoE-producing wild-type bone marrow showed increased plasma IL-1RA levels, and peritoneal macrophages of transplanted animals were shifted to the M2 phenotype (increased IL-1RA production and CD206 expression). Conclusion- apoE signaling via VLDL-R or apoER2 promotes macrophage conversion from the proinflammatory M1 to the antiinflammatory M2 phenotype. This effect may represent a novel antiinflammatory activity of apoE.

Original languageEnglish (US)
Pages (from-to)1160-1168
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number5
DOIs
StatePublished - May 2011

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Apolipoproteins
Apolipoproteins E
Anti-Inflammatory Agents
Macrophages
Low Density Lipoprotein Receptor-Related Protein-1
Phenotype
Interleukins
p38 Mitogen-Activated Protein Kinases
Antibody-Dependent Cell Cytotoxicity
Macrophage Inflammatory Proteins
Cytophagocytosis
Arginase
Interleukin-1 Receptors
LDL Receptors
Peritoneal Macrophages
Nitric Oxide Synthase Type II
Cyclooxygenase 2
Interleukin-12
Protein Kinase Inhibitors
Protein-Tyrosine Kinases

Keywords

  • apolipoproteins
  • inflammation
  • macrophages

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Baitsch, D., Bock, H. H., Engel, T., Telgmann, R., Müller-Tidow, C., Varga, G., ... Nofer, J. R. (2011). Apolipoprotein e induces antiinflammatory phenotype in macrophages. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(5), 1160-1168. https://doi.org/10.1161/ATVBAHA.111.222745

Apolipoprotein e induces antiinflammatory phenotype in macrophages. / Baitsch, Daniel; Bock, Hans H.; Engel, Thomas; Telgmann, Ralph; Müller-Tidow, Carsten; Varga, Georg; Bot, Martine; Herz, Joachim; Robenek, Horst; Von Eckardstein, Arnold; Nofer, Jerzy Roch.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 31, No. 5, 05.2011, p. 1160-1168.

Research output: Contribution to journalArticle

Baitsch, D, Bock, HH, Engel, T, Telgmann, R, Müller-Tidow, C, Varga, G, Bot, M, Herz, J, Robenek, H, Von Eckardstein, A & Nofer, JR 2011, 'Apolipoprotein e induces antiinflammatory phenotype in macrophages', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 5, pp. 1160-1168. https://doi.org/10.1161/ATVBAHA.111.222745
Baitsch, Daniel ; Bock, Hans H. ; Engel, Thomas ; Telgmann, Ralph ; Müller-Tidow, Carsten ; Varga, Georg ; Bot, Martine ; Herz, Joachim ; Robenek, Horst ; Von Eckardstein, Arnold ; Nofer, Jerzy Roch. / Apolipoprotein e induces antiinflammatory phenotype in macrophages. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 ; Vol. 31, No. 5. pp. 1160-1168.
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AU - Engel, Thomas

AU - Telgmann, Ralph

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AU - Varga, Georg

AU - Bot, Martine

AU - Herz, Joachim

AU - Robenek, Horst

AU - Von Eckardstein, Arnold

AU - Nofer, Jerzy Roch

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N2 - Objective- Apolipoprotein E (apoE) exerts potent antiinflammatory effects. Here, we investigated the effect of apoE on the functional phenotype of macrophages. Methods and Results- Human apoE receptors very-low-density lipoprotein receptor (VLDL-R) and apoE receptor-2 (apoER2) were stably expressed in RAW264.7 mouse macrophages. In these cells, apoE downregulated markers of the proinflammatory M1 phenotype (inducible nitric oxide synthase, interleukin [IL]-12, macrophage inflammatory protein-1α) but upregulated markers of the antiinflammatory M2 phenotype (arginase I, SOCS3, IL-1 receptor antagonist [IL-1RA]). In addition, M1 macrophage responses (migration, generation of reactive oxygen species, antibody-dependent cell cytotoxicity, phagocytosis), as well as poly(I:C)- or interferon-γ-induced production of proinflammatory cytokines; cyclooxygenase-2 expression; and activation of nuclear factor-κB, IκB, and STAT1, were suppressed in VLDL-R- or apoER2-expressing cells. Conversely, the suppression of the M2 phenotype and the enhanced response to poly(I:C) were observed in apoE-producing bone marrow macrophages derived from VLDL-R-deficient mice but not wild-type or low-density lipoprotein receptor-deficient mice. The modulatory effects of apoE on macrophage polarization were inhibited in apoE receptor-expressing RAW264.7 cells exposed to SB220025, a p38 mitogen-activated protein kinase inhibitor, and PP1, a tyrosine kinase inhibitor. Accordingly, apoE induced tyrosine kinase-dependent activation of p38 mitogen-activated protein kinase in VLDL-R- or apoER2-expressing macrophages. Under in vivo conditions, apoE mice transplanted with apoE-producing wild-type bone marrow showed increased plasma IL-1RA levels, and peritoneal macrophages of transplanted animals were shifted to the M2 phenotype (increased IL-1RA production and CD206 expression). Conclusion- apoE signaling via VLDL-R or apoER2 promotes macrophage conversion from the proinflammatory M1 to the antiinflammatory M2 phenotype. This effect may represent a novel antiinflammatory activity of apoE.

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