Frontline Science: Activation of metabolic nuclear receptors restores periodontal tissue homeostasis in mice with leukocyte adhesion deficiency-1

Abstract

2 Integrins mediate neutrophil-endothelial adhesion and recruitment of neutrophils to sites of inflammation. The diminished expression of 2 integrins in patients with mutations in the ITGB2 (CD18) gene (leukocyte adhesion deficiency-Type 1; LAD1) results in few or no neutrophils in peripheral tissues. In the periodontium, neutrophil paucity is associated with up-regulation of IL-23 and IL-17, which drive inflammatory bone loss. Using a relevant mouse model, we investigated whether diminished efferocytosis (owing to neutrophil scarcity) is associated with LAD1 periodontitis pathogenesis and aimed to develop approaches to restore the missing efferocytosis signals. We first showed that CD18 −/− mice phenocopied human LAD1 in terms of IL-23/IL-17driven inflammatory bone loss. Ab-mediated blockade of c-Mer tyrosine kinase (Mer), a major efferocytic receptor, mimicked LAD1-associated up-regulation of gingival IL-23 and IL-17 mRNA expression in wild-type (WT) mice. Consistently, soluble Mer-Fc reversed the inhibitory effect of efferocytosis on IL-23 expression in LPS-activated M s. Adoptive transfer of WT neutrophils to CD18 −/− mice down-regulated IL-23 and IL-17 expression to normal levels, but not when CD18 −/− mice were treated with blocking anti-Mer Ab. Synthetic agonist-induced activation of liver X receptors (LXR) and peroxisome proliferator-activated receptors (PPAR), which link efferocytosis to generation of homeostatic signals, inhibited the expression of IL-23 and IL-17 and favorably affected the bone levels of CD18 −/− mice. Therefore, our data link diminished efferocytosisassociated signaling due to impaired neutrophil recruitment to dysregulation of the IL-23-IL-17 axis and, moreover, suggest LXR and PPAR as potential therapeutic targets for treating LAD1 periodontitis.

Role of Porphyromonas gingivalis in oral and orodigestive squamous cell carcinoma

“…106 Epidermal growth factor itself can also be induced by P. gingivalis, which will contribute to the induction of epithelial-mesenchymal transition, as will transforming growth factor beta 1 and tumor necrosis factor, which are also upregulated by P. gingivalis. 77,107 The interleukin-23/interleukin-17 axis, which regulates homeostasis in the periodontium, 108 is strongly protumorigenic, at least in colorectal cancer. 109 P. gingivalis can incite production of these cytokines, 110,111 although the carcinogenic potential has yet to be investigated.…”

Understanding the Role of LFA-1 in Leukocyte Adhesion Deficiency Type I (LAD I): Moving towards Inflammation?

“…In a recent study, the group treated CD18−/− mice with agonists of the transcription factors LXRα/LXRβ (liver X receptors α/β) and PPAR β/δ (peroxisome proliferator-activated receptors β/δ) which are known to promote the resolution of inflammation by the regulation of efferocytosis and neutrophil homeostasis [ 71 , 72 ]. Indeed, pharmacological induction of these receptors resulted in decreased expression of IL-23 and IL-17 and improved bone levels in CD18−/− mice [ 73 ].…”

Intersection between macrophages and periodontal pathogens in periodontitis

“…Of note, Tetsuhiro Kajikawa et al. have shown that impaired efferocytosis, resulting from the loss of β‐integrin (CD18) and the reduction of polymorphonuclear (PMN) recruitment in periodontium, led to an IL‐17/23 axis disorder and caused alveolar bone destruction, 25 suggesting that efferocytosis plays an important role in periodontal tissue homeostasis.…”