Long noncoding RNA (lncRNA) are a class of endogenous, non-protein coding RNAs that are increasingly being associated with various cellular functions and diseases. Yet, despite their ubiquity and abundance, only a minute fraction of these molecules has an assigned function. LncRNAs show tissue-, cell-, and developmental stage-specific expression, and are differentially expressed under physiological or pathological conditions. The role of lncRNAs in the lineage commitment of immune cells and shaping immune responses is becoming evident. Myeloid cells and lymphoid cells are two major classes of immune systems that work in concert to initiate and amplify innate and adaptive immunity in vertebrates. In this review, we provide mechanistic roles of lncRNA through which these noncoding RNAs can directly participate in the differentiation, polarization, and activation of myeloid (monocyte, macrophage, and dendritic cells) and lymphoid cells (T cells, B cells, and NK cells). While our knowledge on the role of lncRNA in immune cell differentiation and function has improved in the past decade, further studies are required to unravel the biological role of lncRNAs and identify novel mechanisms of lncRNA functions in immune cells. Harnessing the regulatory potential of lncRNAs can provide novel diagnostic and therapeutic targets in treating immune cell related diseases.

Aim: Polarization of macrophages (Mφ) is a well‐controlled axis with considerable consequences in both the pro‐inflammatory and resolution phases of inflammation. We aimed to determine if periodontal therapy may instigate M1 to M2 Mφ polarization favoring resolution of inflammation within periodontal tissues.Methods: Gingival biopsies were excised from subjects diagnosed with Stage III, Grade B periodontitis before and 4–6 weeks after nonsurgical periodontal therapy. Total RNA was isolated and pro‐ and anti‐inflammatory markers associated with Mφ polarization assessed by RT‐qPCR. Mice were subject to ligature‐induced periodontitis and gingival tissues collected after 8 days in‐situ or 10 days after ligature removal and M1 and M2 Mφ markers examined by RT‐qPCR and flow cytometry.Results: In human samples, improvement in clinical parameters posttherapy correlates with reduced bacterial burden, downregulation in M1 (TNF‐α, STAT1, CXCL10, and miR‐155), and elevated levels of M2 (STAT6, TGM2, CCL22, and IL‐10) Mφ markers. In a murine model of resolution of LIP, we observed reduced levels of M1 Mφ markers cox2, iNOS2, F4/80+CD80+, and F4/80+CD86+ and elevated levels of M2‐like Mφ markers tgm2, arg1, F4/80+CD206+ and F4/80+CD163+ corroborated human findings.Conclusion: Resolution of periodontal inflammation is associated with M1 to M2 Mφ polarization after nonsurgical periodontal therapy. Assessment of Mφ markers can provide relevant clinical information on the successful response of periodontal therapy and may be used to target nonresponders.

Periodontitis is a multifactorial immune‐mediated disease exacerbated by dysregulated alveolar bone homeostasis. Timely intervention is crucial for disease management to prevent tooth loss. To successfully manage periodontitis, it is imperative to understand the cellular and molecular mechanisms involved in its pathogenesis to develop novel treatment modalities. Non‐surgical periodontal therapy (NSPT) such as subgingival instrumentation/debridement has been the underlying treatment strategy over the past decades. However, new NSPT approaches that target key signaling pathways regulating alveolar bone homeostasis have shown positive clinical outcomes. This narrative review aims to discuss endogenous bone homeostasis mechanisms impaired in periodontitis and highlight the clinical outcomes of preventive periodontal therapy to avoid invasive periodontal therapies. Although the anti‐resorptive therapeutic adjuncts have demonstrated beneficial outcomes, adverse events have been reported. Diverse immunomodulatory therapies targeting the osteoblast/osteoclast (OB/OC) axis have shown promising outcomes in vivo. Future controlled randomized clinical trials (RCT) would help clinicians and patients in the selection of novel preventing therapies targeting key molecules to effectively treat or prevent periodontitis.

Aims: Elevated levels of Herpes Simplex Virus 1 (HSV‐1) have been reported in periodontitis, however, the tropism and relationship with periodontal inflammation are poorly characterized. This study investigated how inflammation affects viral tropism toward human periodontal ligament stem cells (hPDLSCs). Methods: HSV‐1 gB and gD transcripts in healthy and diseased human gingiva were measured by RT‐qPCR and confirmed in HSV‐1‐infected murine gingiva. HSV‐1 infection in hPDLSCs was analyzed by imaging and flow cytometry. hPDLSCs were individually treated with IL‐6, TNF‐α, GMCSF, IL‐10, or PgLPS, and HSV‐1 replication was assessed by infecting with the 17 GFP strain. Lineage markers in virally infected hPDLSCs during osteogenic differentiation were measured by RT‐qPCR and immunofluorescence in vitro and validated in vivo. Mice subjected to ligature‐induced periodontitis (LIP) and infected with HSV‐1 were examined for gingival histology, inflammatory cytokines, and alveolar bone loss. Results: Inflamed human gingiva showed higher expression of viral transcripts compared to healthy controls. In mouse oral HSV‐1 infection, gB and gD expression increased over time, with higher levels in mice with ligature‐induced periodontitis. Virus infected hPDLSCs challenged with inflammatory mediators or PgLPS showed higher GFP, while IL‐10 treatment attenuated GFP levels. Importantly, HSV‐1 17 GFP infection affected osteoblast lineage commitment by promoting the expression of key transcription factors in vitro and in vivo. Compared to the LIP alone group, higher levels of inflammatory markers and bone loss were evident in HSV‐1 infected with LIP. Conclusion: hPDLSCs are trophic to HSV‐1 in vitro and in vivo, with periodontal inflammation playing a significant role in viral tropism.

Introduction: Macrophages (Mφ) can polarize towards the proinflammatory M1 or proresolving M2 phenotype to control diverse biological processes such as inflammation, and tissue regeneration. Noncoding RNAs play critical roles in numerous biological pathways; however, their functional interaction in the regulation of Mφ polarization and immune responses remain unclear. Objectives: To examine relationship between lncRNA (MALAT1) and microRNA (miR-30b) in shaping macrophage polarization and immune functions. Methods: Expression of MALAT1 and miR-30b was examined in differentiating M1/M2 Mφ, human and murine inflamed gingival biopsies by RT-qPCR. MALAT1 and miR-30b direct interaction was examined by dual luciferase assays. Impact of MALAT1 knockdown and miR-30b overexpression was examined on macrophage polarization markers, bacterial phagocytosis, antigen uptake/processing and cytokine profiles. Results: MALAT1 expression displays a time-dependent induction during Mφ differentiation and, upon challenge with TLR4 agonist ( E. coli LPS). Knockdown of MALAT1 enhanced the expression of M2Mφ markers without affecting the M1Mφ markers, suggesting that MALAT1 favors the M1 phenotype by suppressing M2 polarization. MALAT1 knockdown Mφ exhibit reduced antigen uptake and processing, bacterial phagocytosis, and bactericidal activity, strongly supporting its critical role in regulating innate immune functions. Consistent with this, MALAT1 knockdown showed impaired cytokine secretion upon challenge with LPS. Importantly, MALAT1 exhibit an antagonistic expression pattern with all five members of the miR-30 family during M2Mφ differentiation. Dual-luciferase assays validated a novel sequence on MALAT1 that interacts with miR-30b, a microRNA that promotes the M2 phenotype. Phagocytosis and antigen processing assays unequivocally demonstrated that MALAT1 and miR-30b are functionally antagonistic. In human subjects with periodontal disease and murine model of ligature-induced periodontitis, we observed higher levels of MALAT1, and downregulation of miR-30b that correlates with higher M1Mφ markers expression in gingival tissues suggesting a pro-inflammatory function of MALAT1. Conclusion: MALAT1/miR-30b antagonistic interaction shapes Mφ polarization in vitro and in inflamed gingival biopsies.