Gingival spatial analysis reveals geographic immunological variation in a microbiota-dependent and -independent manner.

In mucosal barriers, tissue cells and leukocytes collaborate to form specialized niches that support host-microbiome symbiosis. Understanding the spatial organization of these barriers is crucial for elucidating the mechanisms underlying health and disease. The gingiva, a unique mucosal barrier with significant health implications, exhibits intricate tissue architecture and likely contains specialized immunological regions.

CD47 and thrombospondin-1 contribute to immune evasion by .

is a gram-negative anaerobic bacterium linked to periodontal disease. Remarkably, thrives in an inflamed environment rich in activated neutrophils. Toll-like receptor 2 (TLR2) recognition is required for to evade innate immune killing; however, the mechanisms through which uncouples host inflammation from bactericidal activity are only partially known.

Langerhans cells shape postnatal oral homeostasis in a mechanical-force-dependent but microbiota and IL17-independent manner.

The postnatal interaction between microbiota and the immune system establishes lifelong homeostasis at mucosal epithelial barriers, however, the barrier-specific physiological activities that drive the equilibrium are hardly known. During weaning, the oral epithelium, which is monitored by Langerhans cells (LC), is challenged by the development of a microbial plaque and the initiation of masticatory forces capable of damaging the epithelium. Here we show that microbial colonization following birth facilitates the differentiation of oral LCs, setting the stage for the weaning period, in which adaptive immunity develops.

Porphyromonas gingivalis induction of TLR2 association with Vinculin enables PI3K activation and immune evasion.

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that thrives in the inflamed environment of the gingival crevice, and is strongly associated with periodontal disease. The host response to P. gingivalis requires TLR2, however P.

Microbiota-dependent and -independent postnatal development of salivary immunity.

While saliva regulates the interplay between the microbiota and the oral immune system, the mechanisms establishing postnatal salivary immunity are ill-defined. Here, we show that high levels of neutrophils and neonatal Fc receptor (FcRn)-transferred maternal IgG are temporarily present in the neonatal murine salivary glands in a microbiota-independent manner. During weaning, neutrophils, FcRn, and IgG decrease in the salivary glands, while the polymeric immunoglobulin receptor (pIgR) is upregulated in a growth arrest-specific 6 (GAS6)-dependent manner independent of the microbiota.

Early antitumor activity of oral Langerhans cells is compromised by a carcinogen.

Early diagnosis of oral squamous cell carcinoma (OSCC) remains an unmet clinical need. Therefore, elucidating the initial events of OSCC preceding tumor development could benefit OSCC prognosis. Here, we define the Langerhans cells (LCs) of the tongue and demonstrate that LCs protect the epithelium from carcinogen-induced OSCC by rapidly priming αβT cells capable of eliminating γH2AX epithelial cells, whereas γδT and natural killer cells are dispensable.

Maturation of the neonatal oral mucosa involves unique epithelium-microbiota interactions.

Postnatal host-microbiota interplay governs mucosal homeostasis and is considered to have life-long health consequences. The intestine monolayer epithelium is critically involved in such early-life processes; nevertheless, the role of the oral multilayer epithelium remains ill defined. We demonstrate that unlike the intestine, the neonate oral cavity is immensely colonized by the microbiota that decline to adult levels during weaning.

Intracellular Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells.

is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse and human pancreata harbor microbiota, we explored the involvement of in pancreatic tumorigenesis using cell lines and a xenograft model.

Niche rather than origin dysregulates mucosal Langerhans cells development in aged mice.

Unlike epidermal Langerhans cells (LCs) that originate from embryonic precursors and are self-renewed locally, mucosal LCs arise and are replaced by circulating bone marrow (BM) precursors throughout life. While the unique lifecycle of epidermal LCs is associated with an age-dependent decrease in their numbers, whether and how aging has an impact on mucosal LCs remains unclear. Focusing on gingival LCs we found that mucosal LCs are reduced with age but exhibit altered morphology with that observed in aged epidermal LCs.

Platelet-derived growth factor activates nociceptive neurons by inhibiting M-current and contributes to inflammatory pain.

Endogenous inflammatory mediators contribute to the pathogenesis of pain by acting on nociceptors, specialized sensory neurons that detect noxious stimuli. Here, we describe a new factor mediating inflammatory pain. We show that platelet-derived growth factor (PDGF)-BB applied in vitro causes repetitive firing of dissociated nociceptor-like rat dorsal root ganglion neurons and decreased their threshold for action potential generation.

Myd88 plays a major role in the keratinocyte response to infection with Porphyromonas gingivalis.

Aim: To explore the role of keratinocyte myeloid differentiation primary response 88 (MyD88) expression in the adhesion of Porphyromonas gingivalis to the cells and its subsequent invasion and intracellular survival.

Materials And Methods: Primary mouse keratinocytes from wild-type (WT) or Myd88 mice were infected with P gingivalis alone or co-infected with Fusobacterium nucleatum. Bacterial adhesion and invasion were measured using fluorescent microscopy and flow cytometry, and intracellular survival in keratinocytes was quantified by an antibiotic protection assay.

Mutual interplay between IL-17-producing γδT cells and microbiota orchestrates oral mucosal homeostasis.

γδT cells are a major component of epithelial tissues and play a role in tissue homeostasis and host defense. γδT cells also reside in the gingiva, an oral tissue covered with specialized epithelium that continuously monitors the challenging dental biofilm. Whereas most research on intraepithelial γδT cells focuses on the skin and intestine epithelia, our knowledge on these cells in the gingiva is still incomplete.

Cell-intrinsic regulation of murine epidermal Langerhans cells by protein S.

AXL, a member of the TYRO3, AXL, and MERTK (TAM) receptor tyrosine kinase family, has been shown to play a role in the differentiation and activation of epidermal Langerhans cells (LCs). Here, we demonstrate that growth arrest-specific 6 (GAS6) protein, the predominant ligand of AXL, has no impact on LC differentiation and homeostasis. We thus examined the role of protein S (PROS1), the other TAM ligand acting primarily via TYRO3 and MERTK, in LC function.

Sequential BMP7/TGF-β1 signaling and microbiota instruct mucosal Langerhans cell differentiation.

Mucosal Langerhans cells (LCs) originate from pre-dendritic cells and monocytes. However, the mechanisms involved in their in situ development remain unclear. Here, we demonstrate that the differentiation of murine mucosal LCs is a two-step process.

Porphyromonas gingivalis Promotes Unrestrained Type I Interferon Production by Dysregulating TAM Signaling via MYD88 Degradation.

Whereas type I interferons (IFNs-I) were proposed to be elevated in human periodontitis, their role in the disease remains elusive. Using a bacterial-induced model of murine periodontitis, we revealed a prolonged elevation in IFN-I expression. This was due to the downregulation of TAM signaling, a major negative regulator of IFN-I.

CX3CR1hi Monocyte/Macrophages Support Bacterial Survival and Experimental Infection-Driven Bone Resorption.

Porphyromonas gingivalis,an anaerobic bacterium strongly linked to infection-driven inflammatory bone erosion, thrives within a highly inflamed milieu and disseminates to distant sites, such as atherosclerotic plaque. We examined the role of monocyte/macrophages in determining the outcome of infection with P. gingivalis.

Second-generation Langerhans cells originating from epidermal precursors are essential for CD8+ T cell priming.

In vivo studies questioned the ability of Langerhans cells (LCs) to mediate CD8(+) T cell priming. To address this issue, we used intradermal immunization with plasmid DNA, a system in which activation of CD8(+) T cells depends on delayed kinetics of Ag presentation. We found that dendritic cells (DCs) located in the skin at the time of immunization have limited ability to activate CD8(+) T cells.

Diminished Memory T-Cell Expansion Due to Delayed Kinetics of Antigen Expression by Lentivectors.

Memory CD8(+) T lymphocytes play a central role in protective immunity. In attempt to increase the frequencies of memory CD8(+) T cells, repeated immunizations with viral vectors are regularly explored. Lentivectors have emerged as a powerful vaccine modality with relatively low pre-existing and anti-vector immunity, thus, thought to be ideal for boosting memory T cells.

Langerhans cells down-regulate inflammation-driven alveolar bone loss.

Excessive bone resorption is frequently associated with chronic infections and inflammatory diseases. Whereas T cells were demonstrated to facilitate osteoclastogenesis in such diseases, the role of dendritic cells, the most potent activators of naive T cells, remains unclear. Using a model involving inflammation-driven alveolar bone loss attributable to infection, we showed that in vivo ablation of Langerhans cells (LCs) resulted in enhanced bone loss.

Physiological and molecular evidence of heat acclimation memory: a lesson from thermal responses and ischemic cross-tolerance in the heart.

Sporadic findings in humans suggest that reinduction of heat acclimation (AC) after its loss occurs markedly faster than that during the initial AC session. Animal studies substantiated that the underlying acclimatory processes are molecular. Here we test the hypothesis that faster reinduction of AC (ReAC) implicates "molecular memory.

Acclimatory-phase specificity of gene expression during the course of heat acclimation and superimposed hypohydration in the rat hypothalamus.

The induction of the heat-acclimated phenotype involves reprogramming the expression of genes encoding both constitutive and inducible proteins. In this investigation, we studied the global genomic response in the hypothalamus during heat acclimation, with and without combined hypohydration stress. Rats were acclimated for 2 days (STHA) or for 30 days (LTHA) at 34 degrees C.

Heat intolerance: does gene transcription contribute?

During exertion in the heat, heat-intolerant (HI) subjects have a physiological disability in metabolic heat dissipation. The HI state is either permanent or temporary, depending on whether it stems from transient predisposing factors or inherent thermoregulatory dysfunction. In this investigation, we studied protein levels of heat shock protein (HSP) 70 and HSP72, HSP90, bcl-2xL, glutathione S-transferase-p, heat shock factor-1, TATA-binding protein-associated factor, and NF-kappaB transcripts using Western blot and quantitative RT-PCR, respectively, in lymphocytes of HI and tolerant (T) male volunteers of similar anthropometric features.