Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1
Tomoki Maekawa, Hikaru Tamura, Hisanori Domon, Takumi Hiyoshi, Toshihito Isono, Daisuke Yonezawa, Naoki Hayashi, Naoki Takahashi, Koichi Tabeta, Takeyasu Maeda, Masataka Oda, Athanasios Ziogas, Vasileia Ismini Alexaki, Triantafyllos Chavakis, Yutaka Terao, George Hajishengallis
Tomoki Maekawa, Hikaru Tamura, Hisanori Domon, Takumi Hiyoshi, Toshihito Isono, Daisuke Yonezawa, Naoki Hayashi, Naoki Takahashi, Koichi Tabeta, Takeyasu Maeda, Masataka Oda, Athanasios Ziogas, Vasileia Ismini Alexaki, Triantafyllos Chavakis, Yutaka Terao, George Hajishengallis
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Research Article Immunology Inflammation

Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1

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.

Authors

Tomoki Maekawa, Hikaru Tamura, Hisanori Domon, Takumi Hiyoshi, Toshihito Isono, Daisuke Yonezawa, Naoki Hayashi, Naoki Takahashi, Koichi Tabeta, Takeyasu Maeda, Masataka Oda, Athanasios Ziogas, Vasileia Ismini Alexaki, Triantafyllos Chavakis, Yutaka Terao, George Hajishengallis

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Figure 4

ERM suppresses ligature-induced inflammatory bone loss in a DEL-1–dependent manner.

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ERM suppresses ligature-induced inflammatory bone loss in a DEL-1–depend...
(A) Experimental design. Periodontal bone loss was induced in WT or Del1–/– mice for 9 days by ligating a maxillary second molar and leaving the contralateral tooth unligated (baseline control). Groups of mice were given ERM (20 mg/kg), JSM (20 mg/kg), PC (20 mg/kg), or ethanol control i.p. every day until the day before sacrifice (day 8). (B) Measurements of bone loss in the indicated groups of LIP-subjected mice (left panel; n = 10 mice/group) and representative images of maxillae from each group (right panel). (C) Bone loss was measured in littermate WT or Del1–/– mice that were subjected to LIP and treated with ERM (20 mg/kg) or ethanol control as shown in panel A (n = 10 mice/group). (D) Numbers of neutrophils in the gingiva of LIP-subjected WT mice treated with ethanol control, ERM (20 mg/kg), JSM (20 mg/kg), or PC (20 mg/kg) as described above (n = 6 mice/group). (E) Relative mRNA expression of the indicated molecules in the gingival tissue from LIP-subjected WT mice treated with ERM, JSM, PC, or ethanol control as above. Data were normalized to Gapdh mRNA and are presented as fold change relative to baseline (unligated control), which was set as 1 (n = 6 mice/group). (F) Numbers of neutrophils in the gingival tissue of LIP-subjected WT or Del1–/– mice treated with ERM (20 mg/kg) or ethanol control (n = 6 mice/group). (G) Determination of the protein and mRNA levels of IL-17, IL-6, and IL-10 in the gingival tissue of LIP-subjected WT or Del1–/– mice, which were treated (or not; ethanol control) with 20 mg/kg ERM as outlined in panel A. Protein concentrations (pg cytokines/mg total protein in tissue lysates are shown) and mRNA expression were determined by ELISA and qPCR, respectively. The mRNA data were normalized to Gapdh mRNA and are presented as fold change relative to vehicle-treated WT mice, which was set as 1 (n = 6 mice/group). (H) Tissue sections from LIP-subjected WT mice were stained for DEL-1, neutrophil elastase and nuclei using DAPI. Scale bars, 100 μm. Data are presented as the mean ± SD. *P < 0.01, ***P < 0.0001 by 1-way ANOVA followed by Tukey’s multiple comparisons test (B–G).