Yu Wang

Macrophage polarization toward M1 phenotype (pro-inflammation) is closely associated with the destructive phase of periodontal inflammation. Nanoceria is verified to inhibit M1 polarization of macrophages by the favorable ability of reactive oxygen species (ROS) scavenging. However, the function of nanoceria on macrophage polarization toward M2 phenotype (anti-inflammation) in reparative phase of periodontal inflammation is quite limited. In this work, by introducing an antioxidant drug quercetin onto nano-octahedral ceria, synergistic and intense regulation of host immunity against periodontal disease is realized. Such nanocomposite can control the phenotypic switch of macrophages by not only inhibition of M1 polarization for suppressing the damage in the destructive phase but also promotion of M2 polarization for regenerating the surrounding tissues in reparative phase of periodontal disease. As-prepared nanocomposite can effectively increase the M2/M1 ratio of macrophage polarization in inflammatory cellular models by lipopolysaccharide stimulation. More importantly, the nanocomposite also exerts an improved therapeutic potential against local inflammation by significant downregulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines in an animal model with periodontal inflammation. Therefore, this newly developed nanomedicine is efficient in ROS scavenging and driving pro-inflammatory macrophages to the anti-inflammatory phenotype to eliminate inflammation, thereby providing a promising candidate for treating periodontal inflammation.

BACKGROUND: Porphyromonas gingivalis is a major pathogen of periodontal disease that affects a majority of adults worldwide. Increasing evidence shows that periodontal disease is linked to various systemic diseases like diabetes and cardiovascular disease, by contributing to increased systemic levels of inflammation. Lipopolysaccharides (LPS), as a key virulent attribute of P. gingivalis, possesses significant amount of lipid A heterogeneity containing tetra- (LPS1435/1449) and penta-acylated (LPS1690) structures. Hitherto, the exact molecular mechanism of P. gingivalis LPS involved in periodontal pathogenesis remains unclear, due to limited understanding of the specific receptors and signaling pathways involved in LPS-host cell interactions. METHODOLOGY/PRINCIPAL FINDINGS: This study systematically investigated the effects of P. gingivalis LPS1435/1449 and LPS1690 on the expression of TLR2 and TLR4 signal transduction and the activation of pro-inflammatory cytokines IL-6 and IL-8 in human gingival fibroblasts (HGFs). We found that LPS1435/1449 and LPS1690 differentially modulated TLR2 and TLR4 expression. NF-κB pathway was significantly activated by LPS1690 but not by LPS1435/1449. In addition, LPS1690 induced significant expression of NF-κB and p38 MPAK pathways-related genes, such as NFKBIA, NFKB1, IKBKB, MAP2K4 and MAPK8. Notably, the pro-inflammatory genes including GM-CSF, CXCL10, G-CSF, IL-6, IL-8 and CCL2 were significantly upregulated by LPS1690 while down-regulated by LPS1435/1449. Blocking assays confirmed that TLR4-mediated NF-κB signaling was vital in LPS1690-induced expression of IL-6 and IL-8 in HGFs. CONCLUSIONS/SIGNIFICANCE: The present study suggests that the tetra- and penta-acylated lipid A structures of P. gingivalis LPS differentially activate TLR4-mediated NF-κB signaling pathway, and significantly modulate the expression of IL-6 and IL-8 in HGFs. The ability to alter the lipid A structure of LPS could be one of the strategies carried-out by P. gingivalis to evade innate host defense in gingival tissues, thereby contributing to periodontal pathogenesis.

Seminal studies published in the 1990s and 2000s explored connections between periodontal diseases and systemic conditions, revealing potential contributions of periodontal diseases in the initiation or worsening of systemic conditions. The resulting field of periodontal medicine led to the publication of studies indicating that periodontal diseases can influence the risk of systemic conditions, including adverse pregnancy outcomes, cardiovascular and respiratory diseases, as well as Alzheimer disease and cancers. In general, these studies hypothesized that the periodontal bacterial insult and/or the associated proinflammatory cascade could contribute to the pathogenesis of these systemic diseases. While investigations of the biological basis of the connections between periodontal diseases and systemic conditions generally emphasized the bacteriome, it is also biologically plausible, under an analogous hypothesis, that other types of organisms may have a similar role. Human viruses would be logical "suspects" in this role, given their ubiquity in the oral cavity, association with periodontal diseases, and ability to elicit strong inflammatory response, compromise immune responses, and synergize with bacteria in favor of a more pathogenic microbial consortium. In this review, the current knowledge of the role of viruses in connecting periodontal diseases and systemic conditions is examined. We will also delve into the mechanistic basis for such connections and highlight the importance of those relationships in the management and treatment of patients.

Extracellular vesicles (EVs), including exosomes and microvesicles, are membrane-bound vesicles secreted by most cell types during both physiologic conditions as well in response to cellular stress. EVs play an important role in intercellular communication and are emerging as key players in tumor immunology. Tumor-derived EVs (TDEs) harbor a diverse array of tumor neoantigens and contain unique molecular signature that is reflective of tumor's underlying genetic complexity. As such they offer a glimpse into the immune tumor microenvironment (TME) and have the potential to be a novel, minimally invasive biomarker for cancer immunotherapy. Immune checkpoint inhibitors (ICI), such as anti- programmed death-1(PD-1) and its ligand (PD-L1) antibodies, have revolutionized the treatment of a wide variety of solid tumors including head and neck squamous cell carcinoma, urothelial carcinoma, melanoma, non-small cell lung cancer, and others. Typically, an invasive tissue biopsy is required both for histologic diagnosis and next-generation sequencing efforts; the latter have become more widespread in daily clinical practice. There is an unmet need for noninvasive or minimally invasive (e.g., plasma-based) biomarkers both for diagnosis and treatment monitoring. Targeted analysis of EVs in biospecimens, such as plasma and saliva could serve this purpose by potentially obviating the need for tissue sample. In this review, we describe the current challenges of biomarkers in cancer immunotherapy as well as the mechanistic role of TDEs in modulating antitumor immune response.