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

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

Research output: Contribution to journalArticle

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Abstract

Macrophages become activated by their environment and develop polarized functions: classically activated (M1) macrophages eliminate pathogens but can cause tissue injury, whereas alternatively activated (M2) macrophages promote healing and repair. Mechanisms directing polarized activation, especially in vivo, are not understood completely, and here, we examined the role of SOCS proteins. M2 macrophages activated in vitro or elicited by implanting mice i.p. with the parasitic nematode Brugia malayi display a selective and IL-4-dependent up-regulation of SOCS1 but not SOCS3. Using siRNA-targeted knockdown in BMDM, we reveal that the enhanced SOCS1 is crucial for IL-4-induced M2 characteristics, including a high arginase I:iNOS activity ratio, suppression of T cell proliferation, attenuated responses to IFN-¿/LPS, and curtailed SOCS3 expression. Importantly, SOCS1 was essential in sustaining the enhanced PI3K activity that drives M2 activation, defining a new regulatory mechanism by which SOCS1 controls M2 polarization. By contrast, for M1 macrophages, SOCS1 was not only an important regulator of proinflammatory mediators (IL-6, IL-12, MHC class II, NO), but critically, for M1, we show that SOCS1 also restricted IL-10 secretion and arginase I activity, which otherwise would limit the efficiency of M1 macrophage proinflammatory responses. Together, our results uncover SOCS1, not only as a feedback inhibitor of inflammation but also as a critical molecular switch that tunes key signaling pathways to effectively program different sides of the macrophage balance.
Original languageEnglish
Pages (from-to)845-854
Number of pages10
JournalJournal of Leukocyte Biology
Volume90
Issue number5
Early online date2 May 2011
DOIs
Publication statusPublished - Nov 2011

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Macrophage Activation
Macrophages
Cytokines
Arginase
Interleukin-4
Suppressor of Cytokine Signaling Proteins
Brugia malayi
Interleukin-12
Phosphatidylinositol 3-Kinases
Interleukin-10
Small Interfering RNA
Interleukin-6
Up-Regulation
Cell Proliferation
Inflammation
T-Lymphocytes
Wounds and Injuries

Keywords

  • Animals
  • Arginase
  • Brugia malayi
  • Filariasis
  • Inflammation
  • Interferon-gamma
  • Interleukin-10
  • Interleukin-12
  • Interleukin-4
  • Interleukin-6
  • Lipopolysaccharides
  • Macrophage Activation
  • Macrophages
  • Mice
  • Mice, Inbred BALB C
  • Nitric Oxide Synthase Type II
  • Suppressor of Cytokine Signaling Proteins
  • Up-Regulation
  • Wound Healing

Cite this

Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function. / Whyte, Claire S; Bishop, Eileen T; Rückerl, Dominik; Gaspar-Pereira, Silvia; Barker, Robert N; Allen, Judith E; Rees, Andrew J; Wilson, Heather M.

In: Journal of Leukocyte Biology, Vol. 90, No. 5, 11.2011, p. 845-854.

Research output: Contribution to journalArticle

Whyte, Claire S ; Bishop, Eileen T ; Rückerl, Dominik ; Gaspar-Pereira, Silvia ; Barker, Robert N ; Allen, Judith E ; Rees, Andrew J ; Wilson, Heather M. / Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function. In: Journal of Leukocyte Biology. 2011 ; Vol. 90, No. 5. pp. 845-854.
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AU - Whyte, Claire S

AU - Bishop, Eileen T

AU - Rückerl, Dominik

AU - Gaspar-Pereira, Silvia

AU - Barker, Robert N

AU - Allen, Judith E

AU - Rees, Andrew J

AU - Wilson, Heather M

N1 - Spotlight on Leading Edge Research

PY - 2011/11

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N2 - Macrophages become activated by their environment and develop polarized functions: classically activated (M1) macrophages eliminate pathogens but can cause tissue injury, whereas alternatively activated (M2) macrophages promote healing and repair. Mechanisms directing polarized activation, especially in vivo, are not understood completely, and here, we examined the role of SOCS proteins. M2 macrophages activated in vitro or elicited by implanting mice i.p. with the parasitic nematode Brugia malayi display a selective and IL-4-dependent up-regulation of SOCS1 but not SOCS3. Using siRNA-targeted knockdown in BMDM, we reveal that the enhanced SOCS1 is crucial for IL-4-induced M2 characteristics, including a high arginase I:iNOS activity ratio, suppression of T cell proliferation, attenuated responses to IFN-¿/LPS, and curtailed SOCS3 expression. Importantly, SOCS1 was essential in sustaining the enhanced PI3K activity that drives M2 activation, defining a new regulatory mechanism by which SOCS1 controls M2 polarization. By contrast, for M1 macrophages, SOCS1 was not only an important regulator of proinflammatory mediators (IL-6, IL-12, MHC class II, NO), but critically, for M1, we show that SOCS1 also restricted IL-10 secretion and arginase I activity, which otherwise would limit the efficiency of M1 macrophage proinflammatory responses. Together, our results uncover SOCS1, not only as a feedback inhibitor of inflammation but also as a critical molecular switch that tunes key signaling pathways to effectively program different sides of the macrophage balance.

AB - Macrophages become activated by their environment and develop polarized functions: classically activated (M1) macrophages eliminate pathogens but can cause tissue injury, whereas alternatively activated (M2) macrophages promote healing and repair. Mechanisms directing polarized activation, especially in vivo, are not understood completely, and here, we examined the role of SOCS proteins. M2 macrophages activated in vitro or elicited by implanting mice i.p. with the parasitic nematode Brugia malayi display a selective and IL-4-dependent up-regulation of SOCS1 but not SOCS3. Using siRNA-targeted knockdown in BMDM, we reveal that the enhanced SOCS1 is crucial for IL-4-induced M2 characteristics, including a high arginase I:iNOS activity ratio, suppression of T cell proliferation, attenuated responses to IFN-¿/LPS, and curtailed SOCS3 expression. Importantly, SOCS1 was essential in sustaining the enhanced PI3K activity that drives M2 activation, defining a new regulatory mechanism by which SOCS1 controls M2 polarization. By contrast, for M1 macrophages, SOCS1 was not only an important regulator of proinflammatory mediators (IL-6, IL-12, MHC class II, NO), but critically, for M1, we show that SOCS1 also restricted IL-10 secretion and arginase I activity, which otherwise would limit the efficiency of M1 macrophage proinflammatory responses. Together, our results uncover SOCS1, not only as a feedback inhibitor of inflammation but also as a critical molecular switch that tunes key signaling pathways to effectively program different sides of the macrophage balance.

KW - Animals

KW - Arginase

KW - Brugia malayi

KW - Filariasis

KW - Inflammation

KW - Interferon-gamma

KW - Interleukin-10

KW - Interleukin-12

KW - Interleukin-4

KW - Interleukin-6

KW - Lipopolysaccharides

KW - Macrophage Activation

KW - Macrophages

KW - Mice

KW - Mice, Inbred BALB C

KW - Nitric Oxide Synthase Type II

KW - Suppressor of Cytokine Signaling Proteins

KW - Up-Regulation

KW - Wound Healing

U2 - 10.1189/jlb.1110644

DO - 10.1189/jlb.1110644

M3 - Article

VL - 90

SP - 845

EP - 854

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

SN - 0741-5400

IS - 5

ER -