CCR2+ Macrophages Promote Orthodontic Tooth Movement and Alveolar Bone Remodeling.

Hao Xu,Wen Sun,Bin Yan,Adwait Amod Sathe,Hanwen Zhang,Shuting Zhang,Jiani Guan,Zhichun Jin,Chao Xing

doi:10.3389/fimmu.2022.835986

Abstract

During mechanical force-induced alveolar bone remodeling, macrophage-mediated local inflammation plays a critical role. Yet, the detailed heterogeneity of macrophages is still unknown. Single-cell RNA sequencing was used to study the transcriptome heterogeneity of macrophages during alveolar bone remodeling. We identified macrophage subclusters with specific gene expression profiles and functions. CellChat and trajectory analysis revealed a central role of the Ccr2 cluster during development, with the CCL signaling pathway playing a crucial role. We further demonstrated that the Ccr2 cluster modulated bone remodeling associated inflammation through an NF-κB dependent pathway. Blocking CCR2 could significantly reduce the Orthodontic tooth movement (OTM) progression. In addition, we confirmed the variation of CCR2+ macrophages in human periodontal tissues. Our findings reveal that mechanical force-induced functional shift of the Ccr2 macrophages cluster mediated by NF-κB pathway, leading to a pro-inflammatory response and bone remodeling. This macrophage cluster may represent a potential target for the manipulation of OTM.

Highlights

Orthodontic treatment is a safe and effective option to correct malocclusion of varying classes with the significant limitation of long therapy time
These results suggested that macrophages accumulate and polarize during Orthodontic tooth movement (OTM), which may play an important role in orthodontic remodeling
Comparison of the gene expression profiles and functions of Ccr2 clusters before and after OTM revealed a significant increase of expression of inflammatory markers after OTM

Summary

Introduction

Orthodontic treatment is a safe and effective option to correct malocclusion of varying classes with the significant limitation of long therapy time. Our previous study indicated that macrophages play a crucial role in regulating bone remodeling during OTM [2]. With a highly flexible nature and the ability to rapidly adapt to the local microenvironment, macrophages play an essential role during bone modeling and remodeling by serving as progenitors of osteoclasts, modulators of inflammation, and effectors of mechanical force [3]. Previous studies show that as an essential source of pro-inflammatory cytokines including IL1b, IL-6, TNF-a and GM-CSF both locally and systemically, macrophages are crucial during inflammation-mediated bone remodeling [4]. Recent studies show that M1-like macrophage polarization promotes alveolar bone resorption and consequent OTM after applying mechanical force [5]. The origin, function, and dynamic changes of macrophages during mechanical forceinduced alveolar bone remodeling remain elusive

Methods

Results

Conclusion