Innate Phagocyte Polarization in the Oral Cavity

The oral cavity is a complex environment constantly exposed to antigens from food and the oral microbiota. Innate immune cells play an essential role in maintaining health and homeostasis in the oral environment. However, these cells also play a significant role in disease progression. This review will focus on two innate phagocytes in the oral cavity: macrophages and neutrophils, and examine their roles during homeostasis and disease development, with a focus on periodontal disease and cancer. Macrophages have a well-known ability to polarize and be activated towards a variety of phenotypes. Several studies have found that macrophages’ polarization changes can play an essential role in maintaining health in the oral cavity and contribute to disease. Recent data also finds that neutrophils display phenotypic heterogeneity in the oral cavity. In both cases, we focus on what is known about how these cellular changes alter these immune cells’ interactions with the oral microbiota, including how such changes can lead to worsening, rather than improving, disease states.

Ginsenoside Rb2 Alleviated Atherosclerosis by Inhibiting M1 Macrophages Polarization Induced by MicroRNA-216a

Introduction: Atherosclerosis is a chronic disease characterized by the inflammatory process and lipid depositions. We previously reported that microRNA-216a (miR-216a) can accelerate the progression of atherosclerosis by promoting the polarization of M1 pro-inflammatory phenotype. Ginsenoside Rb2 (Rb2), the major pharmacologically active compound extracted from ginseng, has a high affinity to miR-216a. In this study, we aimed to investigate whether Rb2 can counteract the effect of miR-216a in macrophages to ameliorate atherosclerosis.Methods: The apolipoprotein E deficiency (ApoE−/−) mice model was chronically infected with miR-216a adenovirus via the tail vein and then intraperitoneally injected with Rb2. The plaque lesion area and stability of thoracic aorta were examined. The human myeloid leukemia mononuclear cells (THP-1) or human peripheral blood mononuclear cells (PBMCs) were cultured in vitro, transfected with miR-216a mimics, and treated with Rb2 to explore the mechanisms of Rb2 on the polarization of M1 macrophages, inflammatory process, and lipid accumulation.Results: In the atherosclerotic ApoE−/− mice model, miR-216a greatly increased en face aortic lesion area of the thoracic aorta, lipid accumulation, and M1 macrophages infiltration in plaques, whereas these effects of miR-216a on atherosclerosis burden were significantly alleviated by Rb2 treatment. In the in vitro THP-1 model, the flow cytometry experiment showed that Rb2 treatment inhibited miR-216a–mediated polarization of M1 macrophages characterized by the surface marker CD86 expression but had no effects on M2 polarization characterized by the surface marker CD206 expression. Mechanistically, Rb2 suppressed the miR-216a–mediated inflammatory response through the Smad3/nuclear factor kappa B inhibitor alpha pathway. Moreover, Rb2 reduced the lipid uptake and promoted cholesterol efflux by counteracting the effects of miR-216a in the THP-1–derived foam cells and in the PBMC-derived foam cells under the oxidized low-density lipoproteins.Conclusion: Our findings indicated that Rb2 might be a potential therapeutic molecule for atherosclerosis by attenuating the atherosclerosis plaque lesion, lipid accumulation, and M1 macrophages polarization by targeting miR-216a. Given that accumulation of foam cells in the intima takes place chronically, the role of Rb2 in atherosclerosis progression needs further investigation.

Macrophage Polarization and Plasticity in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that attacks almost every organ. The condition mostly happens to adults but is also found in children, and the latter have the most severe manifestations. Among adults, females, especially non-Caucasian, are mostly affected. Even if the etiology of SLE remains unclear, studies show a close relation between this disease and both genetics and environment. Despite the large number of published articles about SLE, we still do not have a clear picture of its pathogenesis, and no specific drug has been found to treat this condition effectively. The implication of macrophages in SLE development is gaining ground, and studying it could answer these gaps. Indeed, both in vivo and in vitro studies increasingly report a strong link between this disease and macrophages. Hence, this review aims to explore the role of macrophages polarization and plasticity in SLE development. Understanding this role is of paramount importance because in-depth knowledge of the connection between macrophages and this systemic disease could clarify its pathogenesis and provide a foundation for macrophage-centered therapeutic approaches.

Dental Pulp Mesenchymal Stem Cells Promote Polarization of M2 Macrophages and Accelerate Wound Healing by Secreting CCL2

Background Mesenchymal stem cells (MSCs) are widely used in tissue engineering owing to their regenerative potential and immunomodulatory capacity. The crosstalk between MSCs and the host immune function plays a key role in the efficiency of tissue regeneration. However, the difference in immunological modulation and tissue regeneration function between MSCs from different sources remains unclear. Methods Human mesenchymal stem cells derived from bone marrow (BMMSCs), periodontal ligament (PDLSCs), adipose (ADSCs), and dental pulp (DPSCs) were obtained and induced to form cell sheets under the condition of 20 ug/ml vitamin C. The MSC cell sheets carried by hydroxyapatite/tricalciumphosphate (HA/TCP) particles were transplanted subcutaneously into C57BL6 mice for 8 weeks. Histological analyses were performed to detect the tissue regeneration potential and macrophages polarization in vivo. Then, THP-1 macrophages were co-cultured with MSCs and quantitative real-time polymerase chain reaction, immunofluorescent staining, western blotting, and enzyme-linked immunosorbent assay were used to investigate the function and mechanism of MSCs on macrophages in vitro. Finally, a wound healing model of the palatal mucosa was performed to confirm the effect of MSCs on macrophages and tissue healing efficiency. Results Compared to PDLSCs, BMMSCs, and ADSCs, DPSCs exhibited greater tissue regeneration potential, with greater tissue volume, higher Ki67 expression, and less apoptosis in the regenerated tissue of wild-type C57BL6 mice. In addition, DSPCs triggered more M2 macrophages in the regenerated tissue than other MSCs. Our data showed that DPSCs exhibited higher expression levels of C-C Motif Chemokine Ligand 2 (CCL2), and specific blocking of CCL2 by neutralising antibodies can significantly inhibit the DPSCs-induced polarization of M2 macrophages. Finally, DPSCs transplantation promoted wound healing of the palatal mucosa and M2 macrophages polarization in vivo, which could be significantly impaired by CCL2 neutralising antibody. Conclusions Our data indicate that DPSCs exert better tissue regeneration potential and immunoregulatory function by secreting CCL2. These results suggest that CCL2 application can enhance MSC-mediated tissue regeneration or wound healing.

Notch/NICD/RBP-J Signaling Axis Regulates M1 Polarization of Macrophages Mediated by Advanced Glycation End Products

Advanced glycation end products (AGEs) aggregation and macrophages polarization both play essential roles in degenerative bone diseases caused by aging or diabetes, such as senile or diabetic osteoporosis. Here, we aimed to understand the involvement and potential mechanism of AGEs in macrophages polarization and osteoclastogenesis. We found that RAW264.7 macrophages treated with AGEs highly expressed M1-associated genes and surface antigen markers CD86, and released a large amount of NO to the extracellular environment. Through the detection of osteoclast-related markers and TRAP staining, we revealed that the osteoclastogenesis of M1 macrophages could be markedly enhanced by AGEs. To explore the potential mechanisms of AGEs-mediated M1 polarization, we first demonstrated that AGEs effectively activated the transduction of Notch signaling pathway, including nuclear translocation of NICD1. Subsequently, it was observed that the M1 polarization effects induced by AGEs were significantly mitigated, when γ-secretase inhibitor DAPT and siRNA targeting silencing RBP-J were applied to block the signal transduction of Notch. In conclusion, our findings revealed a series of phenomena that AGEs induce macrophage M1 polarization and enhance its osteoclastogenesis ability, and Notch/NICD/RBP-J signaling axis is involved in the regulation of this polarization process.

Cytochrome P450 26A1 Modulates the Polarization of Uterine Macrophages During the Peri-Implantation Period

Uterine M1/M2 macrophages activation states undergo dynamic changes throughout pregnancy, and inappropriate macrophages polarization can cause adverse pregnancy outcomes, especially during the peri-implantation period. Our previous studies have confirmed that Cytochrome P450 26A1 (CYP26A1) can affect embryo implantation by regulating uterine NK cells and DCs. The aim of this study was to investigate whether CYP26A1 regulates the polarization of uterine macrophages in early pregnancy. Here, we observed that Cyp26a1 was significantly upregulated in M1 as compared with M2 of uterine macrophages, Raw264.7 and iBMDM. Knockdown of CYP26A1 in mice uterine significantly decreased the number of embryo implantation sites and the proportion of CD45+F4/80+CD206− M1-like uterine macrophages. Primary uterine macrophages treated with anti-CYP26A1 antibody expressed significantly lower levels of M1 markers Nos2, Il1b, Il6 and Tnf-a. In CYP26A1 knockout Raw264.7 cells, the protein levels of M1 markers TNF-α, IL-6 and CD86 were significantly decreased as compared with the wild type cells. Moreover, CYP26A1 deficiency decreased the ability to produce nitric oxide and increased the phagocytosis capacity of Raw264.7 cells under M1 stimulation state. The re-introduction of CYP26A1 partially reversed the polarization levels of M1 in CYP26A1 knockout Raw264.7 cells. CYP26A1 may regulate the polarization of uterine macrophages to M1 through Stap1 and Slc7a2. In summary, these results indicate that CYP26A1 plays a significant role in macrophage polarization, and knockdown of CYP26A1 can cause insufficient M1 polarization during the peri-implantation period, which has adverse effects on blastocyst implantation.