Systemic analysis of PPARγ in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity

Emmanuel L. Gautier, Andrew Chow, Rainer Spanbroek, Genevieve Marcelin, Melanie Greter, Claudia Jakubzick, Milena Bogunovic, Marylene Leboeuf, Nico Van Rooijen, Andreas J. Habenicht, Miriam Merad, Gwendalyn J. Randolph

Research output: Contribution to journalArticle

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Abstract

Although peroxisome proliferator-activated receptor γ (PPARγ) has anti-inflammatory actions in macrophages, which macrophage populations express PPARγ in vivo and how it regulates tissue homeostasis in the steady state and during inflammation remains unclear.We now show that lung and spleen macrophages selectively expressed PPARγ among resting tissue macrophages. In addition, Ly-6Chi monocytes recruited to an inflammatory site induced PPARγ as they differentiated to macrophages. When PPARγ was absent in Ly-6Chi-derived inflammatory macrophages, initiation of the inflammatory response was unaffected, but full resolution of inflammation failed, leading to chronic leukocyte recruitment. Conversely, PPARγ activation favored resolution of inflammation in a macrophage PPARγ-dependent manner. In the steady state, PPARγ deficiency in red pulp macrophages did not induce overt inflammation in the spleen. By contrast, PPARγ deletion in lung macrophages induced mild pulmonary inflammation at the steady state and surprisingly precipitated mortality upon infection with Streptococcus pneumoniae. This accelerated mortality was associated with impaired bacterial clearance and inability to sustain macrophages locally. Overall, we uncovered critical roles for macrophage PPARγ in promoting resolution of inflammation and maintaining functionality in lung macrophages where it plays a pivotal role in supporting pulmonary host defense. In addition, this work identifies specific macrophage populations as potential targets for the anti-inflammatory actions of PPARγ agonists.

Original languageEnglish (US)
Pages (from-to)2614-2624
Number of pages11
JournalJournal of Immunology
Volume189
Issue number5
DOIs
StatePublished - Sep 1 2012

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Peroxisome Proliferator-Activated Receptors
Immunity
Macrophages
Inflammation
Population
Lung
Anti-Inflammatory Agents
Spleen
Pneumococcal Infections
Mortality
Monocytes
Pneumonia
Leukocytes
Homeostasis

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Gautier, Emmanuel L. ; Chow, Andrew ; Spanbroek, Rainer ; Marcelin, Genevieve ; Greter, Melanie ; Jakubzick, Claudia ; Bogunovic, Milena ; Leboeuf, Marylene ; Van Rooijen, Nico ; Habenicht, Andreas J. ; Merad, Miriam ; Randolph, Gwendalyn J. / Systemic analysis of PPARγ in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity. In: Journal of Immunology. 2012 ; Vol. 189, No. 5. pp. 2614-2624.
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abstract = "Although peroxisome proliferator-activated receptor γ (PPARγ) has anti-inflammatory actions in macrophages, which macrophage populations express PPARγ in vivo and how it regulates tissue homeostasis in the steady state and during inflammation remains unclear.We now show that lung and spleen macrophages selectively expressed PPARγ among resting tissue macrophages. In addition, Ly-6Chi monocytes recruited to an inflammatory site induced PPARγ as they differentiated to macrophages. When PPARγ was absent in Ly-6Chi-derived inflammatory macrophages, initiation of the inflammatory response was unaffected, but full resolution of inflammation failed, leading to chronic leukocyte recruitment. Conversely, PPARγ activation favored resolution of inflammation in a macrophage PPARγ-dependent manner. In the steady state, PPARγ deficiency in red pulp macrophages did not induce overt inflammation in the spleen. By contrast, PPARγ deletion in lung macrophages induced mild pulmonary inflammation at the steady state and surprisingly precipitated mortality upon infection with Streptococcus pneumoniae. This accelerated mortality was associated with impaired bacterial clearance and inability to sustain macrophages locally. Overall, we uncovered critical roles for macrophage PPARγ in promoting resolution of inflammation and maintaining functionality in lung macrophages where it plays a pivotal role in supporting pulmonary host defense. In addition, this work identifies specific macrophage populations as potential targets for the anti-inflammatory actions of PPARγ agonists.",
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Gautier, EL, Chow, A, Spanbroek, R, Marcelin, G, Greter, M, Jakubzick, C, Bogunovic, M, Leboeuf, M, Van Rooijen, N, Habenicht, AJ, Merad, M & Randolph, GJ 2012, 'Systemic analysis of PPARγ in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity', Journal of Immunology, vol. 189, no. 5, pp. 2614-2624. https://doi.org/10.4049/jimmunol.1200495

Systemic analysis of PPARγ in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity. / Gautier, Emmanuel L.; Chow, Andrew; Spanbroek, Rainer; Marcelin, Genevieve; Greter, Melanie; Jakubzick, Claudia; Bogunovic, Milena; Leboeuf, Marylene; Van Rooijen, Nico; Habenicht, Andreas J.; Merad, Miriam; Randolph, Gwendalyn J.

In: Journal of Immunology, Vol. 189, No. 5, 01.09.2012, p. 2614-2624.

Research output: Contribution to journalArticle

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T1 - Systemic analysis of PPARγ in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity

AU - Gautier, Emmanuel L.

AU - Chow, Andrew

AU - Spanbroek, Rainer

AU - Marcelin, Genevieve

AU - Greter, Melanie

AU - Jakubzick, Claudia

AU - Bogunovic, Milena

AU - Leboeuf, Marylene

AU - Van Rooijen, Nico

AU - Habenicht, Andreas J.

AU - Merad, Miriam

AU - Randolph, Gwendalyn J.

PY - 2012/9/1

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N2 - Although peroxisome proliferator-activated receptor γ (PPARγ) has anti-inflammatory actions in macrophages, which macrophage populations express PPARγ in vivo and how it regulates tissue homeostasis in the steady state and during inflammation remains unclear.We now show that lung and spleen macrophages selectively expressed PPARγ among resting tissue macrophages. In addition, Ly-6Chi monocytes recruited to an inflammatory site induced PPARγ as they differentiated to macrophages. When PPARγ was absent in Ly-6Chi-derived inflammatory macrophages, initiation of the inflammatory response was unaffected, but full resolution of inflammation failed, leading to chronic leukocyte recruitment. Conversely, PPARγ activation favored resolution of inflammation in a macrophage PPARγ-dependent manner. In the steady state, PPARγ deficiency in red pulp macrophages did not induce overt inflammation in the spleen. By contrast, PPARγ deletion in lung macrophages induced mild pulmonary inflammation at the steady state and surprisingly precipitated mortality upon infection with Streptococcus pneumoniae. This accelerated mortality was associated with impaired bacterial clearance and inability to sustain macrophages locally. Overall, we uncovered critical roles for macrophage PPARγ in promoting resolution of inflammation and maintaining functionality in lung macrophages where it plays a pivotal role in supporting pulmonary host defense. In addition, this work identifies specific macrophage populations as potential targets for the anti-inflammatory actions of PPARγ agonists.

AB - Although peroxisome proliferator-activated receptor γ (PPARγ) has anti-inflammatory actions in macrophages, which macrophage populations express PPARγ in vivo and how it regulates tissue homeostasis in the steady state and during inflammation remains unclear.We now show that lung and spleen macrophages selectively expressed PPARγ among resting tissue macrophages. In addition, Ly-6Chi monocytes recruited to an inflammatory site induced PPARγ as they differentiated to macrophages. When PPARγ was absent in Ly-6Chi-derived inflammatory macrophages, initiation of the inflammatory response was unaffected, but full resolution of inflammation failed, leading to chronic leukocyte recruitment. Conversely, PPARγ activation favored resolution of inflammation in a macrophage PPARγ-dependent manner. In the steady state, PPARγ deficiency in red pulp macrophages did not induce overt inflammation in the spleen. By contrast, PPARγ deletion in lung macrophages induced mild pulmonary inflammation at the steady state and surprisingly precipitated mortality upon infection with Streptococcus pneumoniae. This accelerated mortality was associated with impaired bacterial clearance and inability to sustain macrophages locally. Overall, we uncovered critical roles for macrophage PPARγ in promoting resolution of inflammation and maintaining functionality in lung macrophages where it plays a pivotal role in supporting pulmonary host defense. In addition, this work identifies specific macrophage populations as potential targets for the anti-inflammatory actions of PPARγ agonists.

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