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

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

doi:10.1172/jci.insight.136706

Cited by 26 publications

(31 citation statements)

References 75 publications

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“…These facts indicate that high levels of ERM in the inflamed tissue may affect surrounding cells such as endothelial cells, osteolineage cells, and certain macrophage subsets in the periodontal tissue. In a previous study, we reported that ERM modulates DEL-1 expression by activating GHSR/JAK2 signaling in vascular endothelial cells [ 21 ]. Consequently, it was suggested that ERM may exert an inhibitory effect on osteoclast differentiation by increasing the expression of DEL-1 in the cells of the periodontal tissue.…”

Section: Discussionmentioning

confidence: 99%

“…We demonstrated that developmental endothelial locus-1 (DEL-1) is a protein that is induced by macrolides and exerts immunomodulatory effects such as suppression of neutrophil migration [ 21 ]. DEL-1 has emerged as an important factor in neutrophil regulation in the context of both the initiation and resolution of inflammation [ 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…Mechanistically, DEL-1 was reported to inhibit the expression of NFATc1 in a Mac-1 integrin-dependent manner [ 25 ]. We recently reported that erythromycin (ERM) exerts its immunomodulatory effects by regulating the local homeostatic factor DEL-1 and reduces bone resorption by inhibiting excessive infiltration of neutrophils in a mouse model [ 21 ]. However, it is not clear whether ERM-induced DEL-1 actually acts on osteoclasts.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Erythromycin on Osteoclasts and Bone Resorption via DEL-1 Induction in Mice

et al. 2021

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Macrolides are used to treat various infectious diseases, including periodontitis. Furthermore, macrolides are known to have immunomodulatory effects; however, the underlying mechanism of their action remains unclear. DEL-1 has emerged as an important factor in homeostatic immunity and osteoclastogenesis. Specifically, DEL-1 is downregulated in periodontitis tissues. Therefore, in the present study, we investigated whether the osteoclastogenesis inhibitory effects of erythromycin (ERM) are mediated through upregulation of DEL-1 expression. We used a ligature-induced periodontitis model in C57BL/6Ncrl wild-type or DEL-1-deficient mice and in vitro cell-based mechanistic studies to investigate how ERM inhibits alveolar bone resorption. As a result of measuring alveolar bone resorption and gene expression in the tooth ligation model, ERM treatment reduced bone loss by increasing DEL-1 expression and decreasing the expression of osteoclast-related factors in wild-type mice. In DEL-1-deficient mice, ERM failed to suppress bone loss and gene expression of osteoclast-related factors. In addition, ERM treatment downregulated osteoclast differentiation and calcium resorption in in vitro experiments with mouse bone marrow-derived macrophages. In conclusion, ERM promotes the induction of DEL-1 in periodontal tissue, which may regulate osteoclastogenesis and decrease inflammatory bone resorption. These findings suggest that ERM may exert immunomodulatory effects in a DEL-1-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Erythromycin on Osteoclasts and Bone Resorption via DEL-1 Induction in Mice

et al. 2021

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“…Systemic antibiotic therapy can enhance the effect of mechanical debridement in overcoming periodontal infections, resulting in clinical improvements, such as a decrease in bleeding on probing, reduction in pocket depth, and gain in clinical attachment level [201,202]. Several reports have demonstrated the effects of systemic antibiotics in a ligature-induced periodontitis mouse model [203][204][205].…”

Section: Effects Of Systemic Antibioticsmentioning

confidence: 99%

Application of Ligature-Induced Periodontitis in Mice to Explore the Molecular Mechanism of Periodontal Disease

Lin

Niimi

Ohsugi

et al. 2021

IJMS

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Periodontitis is an inflammatory disease characterized by the destruction of the periodontium. In the last decade, a new murine model of periodontitis has been widely used to simulate alveolar bone resorption and periodontal soft tissue destruction by ligation. Typically, 3-0 to 9-0 silks are selected for ligation around the molars in mice, and significant bone loss and inflammatory infiltration are observed within a week. The ligature-maintained period can vary according to specific aims. We reviewed the findings on the interaction of systemic diseases with periodontitis, periodontal tissue destruction, the immunological and bacteriological responses, and new treatments. In these studies, the activation of osteoclasts, upregulation of pro-inflammatory factors, and excessive immune response have been considered as major factors in periodontal disruption. Multiple genes identified in periodontal tissues partly reflect the complexity of the pathogenesis of periodontitis. The effects of novel treatment methods on periodontitis have also been evaluated in a ligature-induced periodontitis model in mice. This model cannot completely represent all aspects of periodontitis in humans but is considered an effective method for the exploration of its mechanisms. Through this review, we aimed to provide evidence and enlightenment for future studies planning to use this model.

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“…Microbiota-derived metabolites, short-chain fatty acids (SCFAs), bacterial lipopolysaccharides (LPS), and antimicrobial peptides wield anti-inflammatory or pro-inflammatory effects by acting on immune cells [ 103 , 104 ]. Maekawa et al demonstrated that the anti-inflammatory action of erythromycin is mediated through the upregulation of the secreted homeostatic protein DEL-1 [ 105 ]. Through this study, it was shown that erythromycin regulates neutrophil function in the tissues, such as lungs or the periodontium, in a DEL-1-dependent manner ( Figure 1 ).…”

Section: Antibiotic-associated Shifts In the Gut Microbiotamentioning

confidence: 99%

Effects of Antibiotics upon the Gut Microbiome: A Review of the Literature

et al. 2020

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The human gastrointestinal tract carries a large number of microorganisms associated with complex metabolic processes and interactions. Although antibiotic treatment is crucial for combating infections, its negative effects on the intestinal microbiota and host immunity have been shown to be of the utmost importance. Multiple studies have recognized the adverse consequences of antibiotic use upon the gut microbiome in adults and neonates, causing dysbiosis of the microbiota. Repeated antibiotic treatments in clinical care or low-dosage intake from food could be contributing factors in this issue. Researchers in both human and animal studies have strived to explain this multifaceted relationship. The present review intends to elucidate the axis of the gastrointestinal microbiota and antibiotics resistance and to highlight the main aspects of the issue.

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

Cited by 26 publications

References 75 publications

Effects of Erythromycin on Osteoclasts and Bone Resorption via DEL-1 Induction in Mice

Effects of Erythromycin on Osteoclasts and Bone Resorption via DEL-1 Induction in Mice

Application of Ligature-Induced Periodontitis in Mice to Explore the Molecular Mechanism of Periodontal Disease

Effects of Antibiotics upon the Gut Microbiome: A Review of the Literature

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