Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing
Abstract An inability of neutrophils to eliminate invading microorganisms is frequently associated with severe infection and may contribute to the high mortality rates associated with sepsis. In the present studies, we examined whether metformin and other 5′ adenosine monophosphate-activated protein...
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| Format: | Article |
| Language: | English |
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BMC
2013-10-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.2119/molmed.2013.00065 |
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| author | Dae Won Park Shaoning Jiang Jean-Marc Tadie William S. Stigler Yong Gao Jessy Deshane Edward Abraham Jaroslaw W. Zmijewski |
| author_facet | Dae Won Park Shaoning Jiang Jean-Marc Tadie William S. Stigler Yong Gao Jessy Deshane Edward Abraham Jaroslaw W. Zmijewski |
| author_sort | Dae Won Park |
| collection | DOAJ |
| description | Abstract An inability of neutrophils to eliminate invading microorganisms is frequently associated with severe infection and may contribute to the high mortality rates associated with sepsis. In the present studies, we examined whether metformin and other 5′ adenosine monophosphate-activated protein kinase (AMPK) activators affect neutrophil motility, phagocytosis and bacterial killing. We found that activation of AMPK enhanced neutrophil chemotaxis in vitro and in vivo, and also counteracted the inhibition of chemotaxis induced by exposure of neutrophils to lipopolysaccharide (LPS). In contrast, small interfering RNA (siRNA)-mediated knockdown of AMPKα1 or blockade of AMPK activation through treatment of neutrophils with the AMPK inhibitor compound C diminished neutrophil chemotaxis. In addition to their effects on chemotaxis, treatment of neutrophils with metformin or aminoimidazole carboxamide ribonucleotide (AICAR) improved phagocytosis and bacterial killing, including more efficient eradication of bacteria in a mouse model of peritonitis-induced sepsis. Immunocytochemistry showed that, in contrast to LPS, metformin or AICAR induced robust actin polymerization and distinct formation of neutrophil leading edges. Although LPS diminished AMPK phosphorylation, metformin or AICAR was able to partially decrease the effects of LPS/toll-like receptor 4 (TLR4) engagement on downstream signaling events, particularly LPS-induced IκBα degradation. The IκB kinase (IKK) inhibitor PS-1145 diminished IκBα degradation and also prevented LPS-induced inhibition of chemotaxis. These results suggest that AMPK activation with clinically approved agents, such as metformin, may facilitate bacterial eradication in sepsis and other inflammatory conditions associated with inhibition of neutrophil activation and chemotaxis. Online address: https://doi.org/www.molmed.org |
| first_indexed | 2024-03-12T17:07:52Z |
| format | Article |
| id | doaj.art-10357f9ee8764c019d1f5f4494f2f16e |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-03-12T17:07:52Z |
| publishDate | 2013-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-10357f9ee8764c019d1f5f4494f2f16e2023-08-06T11:17:39ZengBMCMolecular Medicine1076-15511528-36582013-10-0119138739810.2119/molmed.2013.00065Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial KillingDae Won Park0Shaoning Jiang1Jean-Marc Tadie2William S. Stigler3Yong Gao4Jessy Deshane5Edward Abraham6Jaroslaw W. Zmijewski7Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham School of MedicineDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham School of MedicineDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham School of MedicineDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham School of MedicineDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham School of MedicineDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham School of MedicineOffice of the Dean, Wake Forest University School of MedicineDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham School of MedicineAbstract An inability of neutrophils to eliminate invading microorganisms is frequently associated with severe infection and may contribute to the high mortality rates associated with sepsis. In the present studies, we examined whether metformin and other 5′ adenosine monophosphate-activated protein kinase (AMPK) activators affect neutrophil motility, phagocytosis and bacterial killing. We found that activation of AMPK enhanced neutrophil chemotaxis in vitro and in vivo, and also counteracted the inhibition of chemotaxis induced by exposure of neutrophils to lipopolysaccharide (LPS). In contrast, small interfering RNA (siRNA)-mediated knockdown of AMPKα1 or blockade of AMPK activation through treatment of neutrophils with the AMPK inhibitor compound C diminished neutrophil chemotaxis. In addition to their effects on chemotaxis, treatment of neutrophils with metformin or aminoimidazole carboxamide ribonucleotide (AICAR) improved phagocytosis and bacterial killing, including more efficient eradication of bacteria in a mouse model of peritonitis-induced sepsis. Immunocytochemistry showed that, in contrast to LPS, metformin or AICAR induced robust actin polymerization and distinct formation of neutrophil leading edges. Although LPS diminished AMPK phosphorylation, metformin or AICAR was able to partially decrease the effects of LPS/toll-like receptor 4 (TLR4) engagement on downstream signaling events, particularly LPS-induced IκBα degradation. The IκB kinase (IKK) inhibitor PS-1145 diminished IκBα degradation and also prevented LPS-induced inhibition of chemotaxis. These results suggest that AMPK activation with clinically approved agents, such as metformin, may facilitate bacterial eradication in sepsis and other inflammatory conditions associated with inhibition of neutrophil activation and chemotaxis. Online address: https://doi.org/www.molmed.orghttps://doi.org/10.2119/molmed.2013.00065Adenosine Monophosphate-activated Protein Kinase (AMPK)Neutrophil ChemotaxisBacterial KillingAMPK ActivationAminoimidazole Carboxamide Ribonucleotide (AICAR) |
| spellingShingle | Dae Won Park Shaoning Jiang Jean-Marc Tadie William S. Stigler Yong Gao Jessy Deshane Edward Abraham Jaroslaw W. Zmijewski Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing Molecular Medicine Adenosine Monophosphate-activated Protein Kinase (AMPK) Neutrophil Chemotaxis Bacterial Killing AMPK Activation Aminoimidazole Carboxamide Ribonucleotide (AICAR) |
| title | Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing |
| title_full | Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing |
| title_fullStr | Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing |
| title_full_unstemmed | Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing |
| title_short | Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing |
| title_sort | activation of ampk enhances neutrophil chemotaxis and bacterial killing |
| topic | Adenosine Monophosphate-activated Protein Kinase (AMPK) Neutrophil Chemotaxis Bacterial Killing AMPK Activation Aminoimidazole Carboxamide Ribonucleotide (AICAR) |
| url | https://doi.org/10.2119/molmed.2013.00065 |
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