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Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1
Tomoki Maekawa1,2,3, Hikaru Tamura1,2,3, Hisanori Domon1,2
1Center for Advanced Oral Science.
Abstract:
Macrolide antibiotics exert antiinflammatory effects; however, little is known regarding their immunomodulatory mechanisms. In this study, using 2 distinct mouse models of mucosal inflammatory disease (LPS-induced acute lung injury and ligature-induced periodontitis), we demonstrated that the antiinflammatory action of erythromycin (ERM) is mediated through upregulation of the secreted homeostatic protein developmental endothelial locus-1 (DEL-1). Consistent with the anti-neutrophil recruitment action of endothelial cell-derived DEL-1, ERM inhibited neutrophil infiltration in the lungs and the periodontium in a DEL-1-dependent manner. Whereas ERM (but not other antibiotics, such as josamycin and penicillin) protected against lethal pulmonary inflammation and inflammatory periodontal bone loss, these protective effects of ERM were abolished in Del1-deficient mice. By interacting with the growth hormone secretagogue receptor and activating JAK2 in human lung microvascular endothelial cells, ERM induced DEL-1 transcription that was mediated by MAPK p38 and was CCAAT/enhancer binding protein-β dependent. Moreover, ERM reversed IL-17-induced inhibition of DEL-1 transcription, in a manner that was dependent not only on JAK2 but also on PI3K/AKT signaling. Because DEL-1 levels are severely reduced in inflammatory conditions and with aging, the ability of ERM to upregulate DEL-1 may lead to a novel approach for the treatment of inflammatory and aging-related diseases.
Insights
Erythromycin (ERM) reduces inflammation by increasing developmental endothelial locus-1 (DEL-1). This macrolide antibiotic protects against lung and periodontal disease by upregulating DEL-1, offering a potential treatment for inflammatory and aging-related conditions.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Macrolide antibiotics possess anti-inflammatory properties, but their precise immunomodulatory mechanisms remain largely unelucidated.
- Developmental endothelial locus-1 (DEL-1) is a secreted protein with known anti-neutrophil recruitment functions, particularly in endothelial cells.
Purpose of the Study:
- To investigate the immunomodulatory mechanisms underlying the anti-inflammatory effects of erythromycin (ERM).
- To determine the role of developmental endothelial locus-1 (DEL-1) in mediating the protective actions of ERM in mucosal inflammatory diseases.
Main Methods:
- Utilized two distinct mouse models: lipopolysaccharide (LPS)-induced acute lung injury and ligature-induced periodontitis.
- Assessed neutrophil infiltration, bone loss, and survival rates in both wild-type and Del1-deficient mice treated with ERM.
- Investigated molecular pathways, including JAK2, MAPK p38, PI3K/AKT, and CCAAT/enhancer binding protein-β, in human lung microvascular endothelial cells.
Main Results:
- Erythromycin (ERM) demonstrated significant anti-inflammatory effects by upregulating DEL-1 expression in both disease models.
- ERM inhibited neutrophil infiltration and protected against lethal pulmonary inflammation and periodontal bone loss in a DEL-1-dependent manner.
- ERM-induced DEL-1 transcription involved growth hormone secretagogue receptor, JAK2, MAPK p38, and CCAAT/enhancer binding protein-β signaling, and reversed IL-17-mediated inhibition via JAK2 and PI3K/AKT pathways.
Conclusions:
- The anti-inflammatory and protective effects of erythromycin in mucosal inflammatory diseases are critically mediated by the upregulation of developmental endothelial locus-1 (DEL-1).
- Erythromycin's ability to restore DEL-1 levels, which are often diminished in inflammatory conditions and with aging, suggests a novel therapeutic potential.
- Targeting DEL-1 through agents like erythromycin could offer a new strategy for treating a range of inflammatory and age-related diseases.
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