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Interferon Regulatory Factor 2 Plays a Critical Role in Differential Activation of Macrophages
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A2237 - Interferon Regulatory Factor 2 Plays a Critical Role in Differential Activation of Macrophages
Author Block: H. Cui, S. Banerjee, N. Xie, S. Guo, V. J. Thannickal, G. Liu; Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Rationale: Macrophage activations, i.e. the classical and the alternative ones, are well recognized to have crucial roles in inflammation and tissue injury and repair, of which the dysregulation has been widely associated with a number of pulmonary pathologies, such as acute lung injury (ALI) and lung fibrosis. The regulation of macrophage activation has been the focus of recent studies. However, the underlying mechanisms remain incompletely understood. Methods: Mouse alveolar macrophages (AMs) and bone marrow-derived macrophages (BMDMs) were used for in vitro studies. Transfection, RNA sequencing, RNA interference and other cell-based assays were performed. ALI and bleomycin induced lung fibrosis mouse models were utilized. Results: In this study, we found that the expression of interferon regulatory factor 2 (IRF2) was differentially regulated in activated macrophages. IRF2 underwent early degradation in a proteasome-dependent pathway in LPS treated macrophages, while it was transcriptionally induced in IL-4 activated cells. We found that IRF2 was anti-inflammatory in that knockdown of this protein promoted LPS induced proinflammatory mediators. Mechanistically, we found while IRF2 did not target the proximal cytoplasmic signaling events upon LPS engagements, it inhibited HIF-1α dependent expression of glycolytic genes and thereby cellular glycolysis. In contrast, knockdown of IRF2 decreased IL-4 induced alternative activation of macrophages. We found that IRF2 transcriptionally upregulated KLF4, a key mediator of pro-alternative activation. Furthermore, we found that the pro-alternative activation of IRF2 was dependent on KLF4. In relevant in vivo experiments, we found that IRF2 was increased in the lungs of mice with LPS induced ALI, whereas it was decreased in those with bleomycin induced pulmonary fibrosis. Conclusions: Our data suggest that IRF2 is a master regulator of differential activation of macrophages by controlling the key metabolic events and regulators. This study also indicates responsive IRF2 expression as a feed-back mechanism in the lungs to protect from ALI and pulmonary fibrosis.
Author Block: H. Cui, S. Banerjee, N. Xie, S. Guo, V. J. Thannickal, G. Liu; Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Rationale: Macrophage activations, i.e. the classical and the alternative ones, are well recognized to have crucial roles in inflammation and tissue injury and repair, of which the dysregulation has been widely associated with a number of pulmonary pathologies, such as acute lung injury (ALI) and lung fibrosis. The regulation of macrophage activation has been the focus of recent studies. However, the underlying mechanisms remain incompletely understood. Methods: Mouse alveolar macrophages (AMs) and bone marrow-derived macrophages (BMDMs) were used for in vitro studies. Transfection, RNA sequencing, RNA interference and other cell-based assays were performed. ALI and bleomycin induced lung fibrosis mouse models were utilized. Results: In this study, we found that the expression of interferon regulatory factor 2 (IRF2) was differentially regulated in activated macrophages. IRF2 underwent early degradation in a proteasome-dependent pathway in LPS treated macrophages, while it was transcriptionally induced in IL-4 activated cells. We found that IRF2 was anti-inflammatory in that knockdown of this protein promoted LPS induced proinflammatory mediators. Mechanistically, we found while IRF2 did not target the proximal cytoplasmic signaling events upon LPS engagements, it inhibited HIF-1α dependent expression of glycolytic genes and thereby cellular glycolysis. In contrast, knockdown of IRF2 decreased IL-4 induced alternative activation of macrophages. We found that IRF2 transcriptionally upregulated KLF4, a key mediator of pro-alternative activation. Furthermore, we found that the pro-alternative activation of IRF2 was dependent on KLF4. In relevant in vivo experiments, we found that IRF2 was increased in the lungs of mice with LPS induced ALI, whereas it was decreased in those with bleomycin induced pulmonary fibrosis. Conclusions: Our data suggest that IRF2 is a master regulator of differential activation of macrophages by controlling the key metabolic events and regulators. This study also indicates responsive IRF2 expression as a feed-back mechanism in the lungs to protect from ALI and pulmonary fibrosis.
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