Langerhans cells down-regulate inflammation-driven alveolar bone loss

Arizon, Moran; Nudel, Itay; Segev, Hadas; Mizraji, Gabriel; Elnekave, Mazal; Furmanov, Karina; Eli-Berchoer, Luba; Clausen, Björn E.; Shapira, Lior; Wilensky, Asaf; Hovav, Avi‐Hai

doi:10.1073/pnas.1116770109

Cited by 62 publications

(97 citation statements)

References 49 publications

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“…Nevertheless, the ability of GAS6 to modulate polarization of Treg/Th17 in DCs in vivo is instructed by signals initiated by epithelial cells, because the absence of Gas6 in hematopoietic cells alone (Gas6 −/− → WT) had no significant impact on the mice. Previous studies have shown that Th17 and Treg cells play an important role in the development of experimental periodontitis (29,30). It was also suggested that periodontitis could be a result of oral microbial dysbiosis induced by periodontal pathogens (20).…”

Section: Discussionmentioning

confidence: 99%

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Nassar

Tabib

Capucha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3–AXL–MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3–4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive nitrogen species. We also found an imbalance in Th17/Treg ratio known to control tissue homeostasis, as Gas6-deficient dendritic cells preferentially secreted IL-6 and induced Th17 cells. As a result of this immunological shift, a significant microbial dysbiosis was observed in Gas6−/− mice, because anaerobic bacteria largely expanded by using inflammatory byproducts for anaerobic respiration. Using chimeric mice, we found a critical role for GAS6 in epithelial cells in maintaining oral homeostasis, whereas its absence in hematopoietic cells synergized the level of dysbiosis. We thus propose GAS6 as a key immunological regulator of host–commensal interactions in the oral epithelium.

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Section: Discussionmentioning

confidence: 99%

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Nassar

Tabib

Capucha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…DCs play an essential role in resistance to infection by their ability to present bacterial antigen to lymphocytes, initiating the adaptive immune response (Cutler and Teng 2007;Hovav 2014). The interactions between DCs and other cells of the innate and adaptive immune responses are thought to be important in the pathogenesis of periodontal disease (Arizon et al 2012). DC function is regulated by transcription factors, including FOXO1.…”

Section: Introductionmentioning

confidence: 99%

Effect of Aging on Periodontal Inflammation, Microbial Colonization, and Disease Susceptibility

Dong

Xiao

et al. 2016

J Dent Res

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Periodontitis is a chronic inflammatory disease induced by a biofilm that forms on the tooth surface. Increased periodontal disease is associated with aging. We investigated the effect of aging on challenge by oral pathogens, examining the host response, colonization, and osteoclast numbers in aged versus young mice. We also compared the results with mice with lineage-specific deletion of the transcription factor FOXO1, which reduces dendritic cell (DC) function. Periodontitis was induced by oral inoculation of Porphyromonas gingivalis and Fusobacterium nucleatum in young (4 to 5 mo) and aged (14 to 15 mo) mice. Aged mice as well as mice with reduced DC function had decreased numbers of DCs in lymph nodes, indicative of a diminished host response. In vitro studies suggest that reduced DC numbers in lymph nodes of aged mice may involve the effect of advanced glycation end products on DC migration. Surprisingly, aged mice but not mice with genetically altered DC function had greater production of antibody to P. gingivalis, greater IL-12 expression, and more plasma cells in lymph nodes following oral inoculation as compared with young mice. The greater adaptive immune response in aged versus young mice was linked to enhanced levels of P. gingivalis and reduced bacterial diversity. Thus, reduced bacterial diversity in aged mice may contribute to increased P. gingivalis colonization following inoculation and increased periodontal disease susceptibility, reflected by higher TNF levels and osteoclast numbers in the periodontium of aged versus young mice.

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“…It was shown that LCs can prime CD4 + Th17 cells under inflammatory conditions, as well as Th2 responses via thymic stromal lymphopoietin signaling (3,4). LCs also can limit adaptive immune responses by stimulating the differentiation of T regulatory cells (5)(6)(7). In contrast to CD4 + T cells, LCs were shown to be dispensable for CD8 + T cell priming in numerous experimental systems (8)(9)(10)(11).…”

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confidence: 99%

Second-Generation Langerhans Cells Originating from Epidermal Precursors Are Essential for CD8+ T Cell Priming

Elnekave

Furmanov

Shaul

et al. 2014

The Journal of Immunology

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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. This activity was mediated by a second generation of DCs that differentiated in the skin several days after immunization, as well as by lymph node–resident DCs. Intriguingly, CD8+ T cell responses were not affected following treatment with clodronate liposomes, immunization of CCR2−/− mice, or local neutralization of CCL20. This suggests that local, rather than blood-derived, DC precursors mediate CD8+ T cell priming. Analysis of DC differentiation in the immunized skin revealed a gradual increase in the number of CD11c+ cells, which reached their maximum 2 wk after immunization. A similar differentiation kinetics was observed for LCs, with the majority of differentiating LCs proliferating in situ from epidermal precursors. By using B6/Langerin–diphtheria toxin receptor chimeric mice and LC ablation, we demonstrated that epidermal LCs were crucial for the elicitation of CD8+ T cell responses in vivo. Furthermore, LCs isolated from lymph nodes 2 wk after immunization contained the immunization plasmid and directly activated Ag-specific CD8+ T cells ex vivo. Thus, these results indicate that second-generation Ag-expressing LCs differentiating from epidermal precursors directly prime CD8+ T cells and are essential for optimal cellular immune responses following immunization with plasmid DNA.

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Langerhans cells down-regulate inflammation-driven alveolar bone loss

Cited by 62 publications

References 49 publications

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Effect of Aging on Periodontal Inflammation, Microbial Colonization, and Disease Susceptibility

Second-Generation Langerhans Cells Originating from Epidermal Precursors Are Essential for CD8+ T Cell Priming

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