Macrophage ATF6 Accelerates Orthodontic Tooth Movement through Promoting Tnfa Transcription

Corticotomy is a clinical procedure targeting alveolar bone to activate regional acceleratory phenomenon (RAP) and promote orthodontic tooth movement (OTM). Corticotomy involves the orchestration of inflammation by macrophages, but the underlying mechanism remains unclear. Here, we identify endoplasmic reticulum (ER) stress sensor activating transcription factor 6 (ATF6) as a critical player modulating pro- and anti-inflammatory macrophage polarization. We show that macrophage-specific ATF6 deletion blocks corticotomy-induced OTM acceleration, while macrophage ATF6 overexpression exaggerates the acceleration effect. Furthermore, the proportion of pro-inflammatory macrophages is positively correlated with ATF6 expression in vitro and in vivo. By RNA-seq and CUT&Tag, we demonstrate that ATF6 interacts with Tnfa promotor and augments its transcription, thereby mediating the effect of TNF signaling pathway in pro-inflammatory macrophage polarization. In summary, ATF6 may aggravate alveolar bone remodeling during corticotomy by promoting Tnfa transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerating orthodontics. Overall design: To investigate the mechanism by which ATF6 influences macrophage pro-inflammatory function, we sought to identify candidate target inflammatory cytokines of ATF6 p50 in BMDMs using Cleavage Under Targets & Tagmentation (CUT&Tag) assay. To this end, BMDMs were stimulated with alveolar bone lysates from BLANK, TM, and TM+CO models for 3 hours.