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

Tabib, Yaara; Jaber, Nora; Nassar, Maria; Capucha, Tal; Mizraji, Gabriel; Nir, Tsipora; Koren, Noam; Aizenbud, Itay; Maimon, Avi; Eli-Berchoer, Luba; Wilensky, Asaf; Burstyn‐Cohen, Tal; Hovav, Avi‐Hai

doi:10.1073/pnas.1800303115

Cited by 14 publications

(16 citation statements)

References 36 publications

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“…We next used an in vitro screen to identify the growth factors, in addition to TGFβ, that controlled Id2 expression and LC identity after differentiation from BM cells. We selected BMP7, CSF-1 and IL-34 based on expression of their cognate receptors (BMPR1a and CSF1R respectively) by EpCAM + cells in vivo (Figure S5G) and their requirement for LC repopulation after UV-irradiation (43, 49, 50), and tested the impact of each factor on LC development in BM cultures (Figure S6) (20, 41, 51). IL-34, but not CSF-1 or BMP7 enhanced LC numbers (Figure 6C), and this was associated with the specific up-regulation of Id2 by LC in IL-34 cultures (Figure 6D).…”

Section: Resultsmentioning

confidence: 99%

A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury

et al. 2019

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A dense population of embryo-derived Langerhans cells (eLCs) is maintained within the sealed epidermis without contribution from circulating cells. When this network is perturbed by transient exposure to ultraviolet light, short-term LCs are temporarily reconstituted from an initial wave of monocytes but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this process is relevant to immunopathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where alloreactive T cells directly target eLCs, we have asked whether and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of long-term LCs in this context. Destruction of eLCs leads to recruitment of a wave of monocytes that engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+precursors. Monocyte-derived LCs acquire the capacity of self-renewal, and proliferation in the epidermis matched that of steady-state eLCs. However, we identified a bottleneck in the differentiation and survival of epidermal monocytes, which, together with the slow rate of renewal of mature LCs, limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.

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Section: Resultsmentioning

confidence: 99%

A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury

et al. 2019

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“…BM cells eluted from the bone by flushing them several times using sterile syringe filled with RPMI 1640, and the cells were then washed, treated with ACK solution for 3 min on ice, washed again and counted. BM cells (5 × 10 5 cells/well) in 24-well plates (Nunc) were cultured with complete RPMI media [450 ml RPMI 1640, 50 ml FCS, 5 ml l -glutamine, 50 µM β-mercaptoethanol, penicillin (100 U/ml), streptomycin (100 µg/ml), and gentamicin (50 µg/ml)] supplemented with GM-SCF (100 ng/ml), TGF-β1 (10 ng/ml) for 5 days to induce their differentiation into LC-like cells as previously described ( 31 ). To examine the impact of Ti ions on LC, we applied Ti standard solution (1,000 µg/ml Ti in H 2 O, Sigma), at day 0, in various dilutions to the cultures.…”

Section: Methodsmentioning

confidence: 99%

Impaired Differentiation of Langerhans Cells in the Murine Oral Epithelium Adjacent to Titanium Dental Implants

et al. 2018

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Peri-implantitis is a destructive inflammatory process affecting tissues surrounding dental implants and it is considered a new global health concern. Human studies have suggested that the frequencies of Langerhans cells (LCs), the main antigen-presenting cells (APCs) of the oral epithelium, are dysregulated around the implants. Since LCs play a role in regulating oral mucosal homeostasis, we studied the impact of dental titanium implants on LC differentiation using a novel murine model. We demonstrate that whereas the percentage of LC precursors (CD11c+MHCII+) increased in the peri-implant epithelium, the frequencies of LCs (CD11c+MHCII+EpCAM+langerin+) were significantly reduced. Instead, a population of partially developed LCs expressing CD11c+MHCII+EpCAM+ but not langerin evolved in the peri-implant mucosa, which was also accompanied by a considerable leukocyte infiltrate. In line with the increased levels of LC precursors, expression of CCL2 and CCL20, chemokines mediating their translocation to the epithelium, was elevated in the peri-implant epithelium. However, expression of TGF-β1, the major cytokine driving final differentiation of LCs, was reduced in the epithelium. Further analysis revealed that while the expression of the TGF-β1 canonical receptor activing-like kinase (ALK)5 was upregulated, expression of its non-canonical receptor ALK3 was decreased. Since titanium ions releasing from implants were proposed to alter APC function, we next analyzed the impact of such ions on TGF-β1-induced LC differentiation cultures. Concurring with the in vivo studies, the presence of titanium ions resulted in the generation of partially developed LCs that express CD11c+MHCII+EpCAM+ but failed to upregulate langerin expression. Collectively, these findings suggest that titanium dental implants have the capacity to impair the development of oral LCs and might subsequently dysregulate immunity in the peri-implant mucosa.

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“…Culture of BM cells with GM-CSF led to the expansion of Flt3 + and CD115 + cDC and moDC, and CD115 + macrophages, based on the gating strategy published by the Reis e Sousa group ( Figure S2) (41). By comparison, culture of BM cells with GM-CSF and TGFβ to generate BM-LC (20,43,44) demonstrate a more heterogeneous profile within EpCAM + DEC205 + cells with subsets of both CD115 + and CD115 neg cells. However, there was no contribution of CD135 + cells to the LC-like cells in these cultures, mirroring our in vivo findings ( Figure 2D).…”

Section: Lineage Cells Do Not Become Long-term Replacement Lcmentioning

confidence: 99%

A single wave of monocytes is sufficient to replenish the long-term Langerhans cell network after immune injury

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et al. 2019

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Embryo-derived Langerhans cells (eLC) are maintained within the sealed epidermis without contribution from circulating cells. When the network is perturbed by transient exposure to ultra-violet light, short-term LC are temporarily reconstituted from an initial wave of monocytes, but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this mechanism is relevant to immune-pathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where allo-reactive T cells directly target eLC, we have asked if and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of the long-term LC in this context. Destruction of eLC leads to recruitment of a single wave of monocytes which engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+ precursors. Monocyte-derived LC acquire the capacity of self-renewal, and turn-over in the epidermis was remarkably similar to that of steady state eLC. However, we have identified a bottleneck in the differentiation and survival of epidermal monocytes, which together with the slow turn-over of mature LC limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin. Highlights Immune injury leads to recruitment of a single wave of monocytes to replace resident Langerhans cells (LC). DC lineage cells cannot become long-term replacement LC. The size of the re-emerging network is controlled by density-dependent division of mature LC. Immune injury and inefficient repopulation by monocyte-derived cells lead to a permanently altered LC niche.

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

Cited by 14 publications

References 36 publications

A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury

A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury

Impaired Differentiation of Langerhans Cells in the Murine Oral Epithelium Adjacent to Titanium Dental Implants

A single wave of monocytes is sufficient to replenish the long-term Langerhans cell network after immune injury

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