CD301b+ macrophage: the new booster for activating bone regeneration in periodontitis treatment

Abstract

Periodontal bone regeneration is a major challenge in the treatment of periodontitis. Currently the main obstacle is the difficulty of restoring the regenerative vitality of periodontal osteoblast lineages suppressed by inflammation, via conventional treatment. CD301b+ macrophages were recently identified as a subpopulation that is characteristic of a regenerative environment, but their role in periodontal bone repair has not been reported. The current study indicates that CD301b+ macrophages may be a constituent component of periodontal bone repair, and that they are devoted to bone formation in the resolving phase of periodontitis. Transcriptome sequencing suggested that CD301b+ macrophages could positively regulate osteogenesis-related processes. In vitro, CD301b+ macrophages could be induced by interleukin 4 (IL-4) unless proinflammatory cytokines such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were present. Mechanistically, CD301b+ macrophages promoted osteoblast differentiation via insulin-like growth factor 1 (IGF-1)/thymoma viral proto-oncogene 1 (Akt)/mammalian target of rapamycin (mTOR) signaling. An osteogenic inducible nano-capsule (OINC) consisting of a gold nanocage loaded with IL-4 as the “core” and mouse neutrophil membrane as the “shell” was designed. When injected into periodontal tissue, OINCs first absorbed proinflammatory cytokines in inflamed periodontal tissue, then released IL-4 controlled by far-red irradiation. These events collectively promoted CD301b+ macrophage enrichment, which further boosted periodontal bone regeneration. The current study highlights the osteoinductive role of CD301b+ macrophages, and suggests a CD301b+ macrophage-targeted induction strategy based on biomimetic nano-capsules for improved therapeutic efficacy, which may also provide a potential therapeutic target and strategy for other inflammatory bone diseases.

Tim4 deficiency reduces CD301b+ macrophage and aggravates periodontitis bone loss

“…5 a, b), validating our previous inducing strategy. 20 Tim4 overexpression further markedly increased the percentages of CD301b + macrophages (Fig. 5 a, b).…”

“…1a ). 20 The transcriptomes of CD301b + macrophages and CD301b − macrophages were compared, and significantly upregulated transcription level of Timd4 (gene name of Tim4) in CD301b + macrophages was illustrated in the heatmap (Fig. 1b ).…”

“…Insulin-like growth factor 1 (Igf1) was one of the most essential growth factors for bone remodeling and has been described as the representative functional molecule of CD301b + macrophages. 20 , 31 Accordingly, we next explored whether the overexpression of Tim4 altered Igf1 protein level utilizing Western blot. The expression of Igf1 was upregulated via IL-4 stimulation, which was further enhanced after Tim4 overexpression (Fig.…”

“… 15 – 18 Our recent research investigated the role of CD301b + macrophages in periodontal bone remodeling. 19 , 20 Interestingly, we revealed that CD301b + macrophages might play an active role in orthodontic treatments under inflammatory periodontitis condition. 19 Moreover, we reported that depletion of CD301b + macrophages caused more serious bone destruction in the Mgl2-DTR mice (Mgl2, macrophage galactose N-acetyl-galactosamine specific lectin 2 gene encoding the CD301b protein) periodontitis model.…”

“…19 Moreover, we reported that depletion of CD301b + macrophages caused more serious bone destruction in the Mgl2-DTR mice (Mgl2, macrophage galactose N-acetyl-galactosamine specific lectin 2 gene encoding the CD301b protein) periodontitis model. 20 Nonetheless, the key upstream targets of CD301b + macrophages remain elusive to date. Thus, it is important to figure out the strategy to specifically activate CD301b + macrophages, which may help to develop the new immunomodulatory therapeutic targets for periodontitis.…”