Immunorthodontics: PD-L1, a Novel Immunomodulator in Cementoblasts, Is Regulated by HIF-1α under Hypoxia

Abstract

Recent studies have revealed that hypoxia alters the PD-L1 expression in periodontal cells. HIF-1α is a key regulator for PD-L1. As hypoxia presents a hallmark of an orthodontically induced microenvironment, hypoxic stimulation of PD-L1 expression may play vital roles in immunorthodontics and orthodontically induced inflammatory root resorption (OIIRR). This study aims to investigate the hypoxic regulation of PD-L1 in cementoblasts, and its interaction with hypoxia-induced HIF-1α expression. The cementoblast (OCCM-30) cells (M. Somerman, NIH, NIDCR, Bethesda, Maryland) were cultured in the presence and absence of cobalt (II) chloride (CoCl2). Protein expression of PD-L1 and HIF-1α as well as their gene expression were evaluated by Western blotting and RT-qPCR. Immunofluorescence was applied to visualize the localization of the proteins within cells. The HIF-1α inhibitor (HY-111387, MedChemExpress) was added, and CRISPR/Cas9 plasmid targeting HIF-1α was transferred for further investigation by flow cytometry analysis. Under hypoxic conditions, cementoblasts undergo an up-regulation of PD-L1 expression at protein and mRNA levels. Silencing of HIF-1α using CRISPR/Cas9 indicated a major positive correlation with HIF-1α in regulating PD-L1 expression. Taken together, these findings show the influence of hypoxia on PD-L1 expression is modulated in a HIF-1α dependent manner. The HIF-1α/PD-L1 pathway may play a role in the immune response of cementoblasts. Thus, combined HIF-1α/PD-L1 inhibition could be of possible therapeutic relevance for OIIRR prevention.

Retrospective Analysis of the Predictive Value of 18F-FDG PET/CT Metabolic Parameters for PD-L1 Expression in Cervical Cancer

“…It has been reported by some previous researchers that HIF-1α plays an important role in triggering the glycolysis of tumor cells and enhancing their 18 F-FDG uptake [ 35 , 36 , 37 ]. In addition, HIF-1α could upregulate PD-L1 expression by binding directly to the hypoxia-responsive element (HRE) in the PD-L1 promoter [ 38 , 39 , 40 ]. According to these findings, the positive correlation between PD-L1 expression and 18 F-FDG accumulation could be mostly resulting from the activation of HIF-1α pathway.…”

Ciliary Neurotrophic Factor (CNTF) Inhibits In Vitro Cementoblast Mineralization and Induces Autophagy, in Part by STAT3/ERK Commitment

“…The growth medium was replaced every day with fresh medium. Until grown of adherently cementoblasts to 80% confluency, the concentration of FBS was set to 0.5% as a starvation medium 14 h prior to CNTF stimulation [ 30 ]. All experiments were performed using cells at the 2nd to 5th passages.…”

PD-L1, a Potential Immunomodulator Linking Immunology and Orthodontically Induced Inflammatory Root Resorption (OIIRR): Friend or Foe?

“…It has been demonstrated to be up-regulated upon immune activation conditions, such as inflammations [ 83 ]. In recent studies, we identified for the first time that PD-L1 is induced and constantly expressed on murine cementoblasts in response to compression and hypoxia, simulating orthodontic-force-induced microenvironmental changes [ 84 , 85 ]. In detail, the recent data revealed that the application of a compressive force at a magnitude of 2.4 gf/cm 2 enhances the PD-L1 expression in cementoblasts.…”

“…In addition, it was revealed that HIF-1α plays an pivotal role in the PD-L1 modulation [ 84 ]. Another very recent study conducted by our group showed that long-term exposure to hypoxic conditions augmented PD-L1 expression on cementoblasts [ 85 ]. Based on these observations, it is reasonable to hypothesize that this ligand could serve as a potential target for therapies aimed at anti-OIIRR [ 86 ] ( Figure 3 ).…”