Cutaneous RANK–RANKL Signaling Upregulates CD8-Mediated Antiviral Immunity during Herpes simplex Virus Infection by Preventing Virus-Induced Langerhans Cell Apoptosis

Klenner, Lars; Hafezi, Wali; Clausen, Björn E.; Lorentzen, Eva; Luger, Thomas A.; Beissert, Stefan; Kühn, Joachim; Loser, Karin

doi:10.1038/jid.2015.225

Cited by 10 publications

(13 citation statements)

References 45 publications

(73 reference statements)

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“…There is a little information regarding activity pathway and role of RANKL in immune system in birds and mammals during parasite infection. It has been reported that RANK-RANKL is crucial in the priming of antiviral immunity and improving antigen transport to regional lymph nodes in mice infected with Herpes virus-type 1 (Klenner et al, 2015). In the current study, increased serum RANKL in response to the Eimeria challenge was correlated with the tibia mineral loss ( P < 0.05).…”

Section: Discussionmentioning

confidence: 99%

Eimeria challenge adversely affected long bone attributes linked to increased resorption in 14-day-old broiler chickens

Kakhki

Thanabalan

et al. 2019

Poultry Science

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There is limited information on the effects of enteric pathogen on bone quality in rapidly growing broiler chicks. We examined tibia and femur attributes (length, diameter, relative weight of ash content [AC] to the BW, ash concentration [AP]) and serum bone-turnover markers including receptor activator of nuclear factor kappa-B ligand (RANKL) for resorption, alkaline phosphatase (ALP) for mineralization, and selected serum metabolites in 14-day-old broilers challenged with Eimeria. A total of 160 (80 males and 80 females) 1-day-old Ross × Ross 708 chicks were used. Based on BW, birds were placed within sex in cages (5 birds per cage) and fed chick starter diets to day 9 of age. On day 9, half of the cages were orally gavaged with 1 mL of Eimeria culture (100,000 oocysts of E. acervulina and 25,000 oocysts of E. maxima) and the other half (unchallenged control) received 1 mL 0.9% saline in distilled water. On day 14, 2 birds were randomly selected and necropsied for intestinal lesion score, blood, tibia, and femur samples. Data were analyzed in a 2 (challenged vs. unchallenged) × 2 (males vs. females) factorial arrangement. There was no interaction (P > 0.05) between Eimeria and sex on any measurement. Whereas there were no intestinal lesions in unchallenged birds, Eimeria resulted in lesion score (0 to 4) of 3.35, 2.59 and 0.11 in duodenum, jejunum and ileum, respectively. Eimeria challenge decreased (P < 0.05) tibia AC and AP by 10 and 8.2%, respectively but had no (P > 0.10) effect on femur attributes. Generally, males showed (P < 0.05) longer and wider bones with more AC compared with the female. Circulating serum RANKL concentration increased (P = 0.017) in response to Eimeria challenge and was negatively correlated with tibia AC (–0.731; P = 0.021). Our findings showed that Eimeria damage to the intestinal physiology had adverse effects on long bone attributes linked to increased resorption.

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Section: Discussionmentioning

confidence: 99%

Eimeria challenge adversely affected long bone attributes linked to increased resorption in 14-day-old broiler chickens

Kakhki

Thanabalan

et al. 2019

Poultry Science

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“…This in turn is associated with an improved induction of MHC class I-restricted HSV-1-specific antiviral immunity, dependent on TLR3 signaling. [12] NF-κB also appears to be important for human LC activation through TLR2 signaling, resulting in up-regulation of CD86, CD83, CCR7, TNF and IL-6, and the priming of CD4 T cell responses. [95] Thus, it is likely, that while EpCAM -β-catenin -IRF4 regulatory circuit controls tolerogenic LC function, proinflammatory signaling from keratinocytes or danger signals from pathogen derived components and PRR activation, program the immunogenic state of LCs via IRF1 and NF-κB.…”

Section: Lc Immunogenicity Is Promoted By the Transcription Factors Imentioning

confidence: 99%

“…Murine LCs have been shown to generate potent T cell responses to cutaneous pathogens, including herpes simplex virus (HSV) and Staphylococcus aureus. [ 11–13 ] Langerin (CD207), the LC hallmark molecule, has been implicated in both human and murine LCs to recognize opportunistic and pathogenic fungi, including Candida species and Malassezia furfur . [ 14,15 ] We and others have demonstrated that human LCs can efficiently prime CD4 T cell responses and also induce naïve CD8 T cell activation via antigen presentation as well as cross‐ presentation, respectively.…”

Section: Langerhans Cells Induce Tolerogenic As Well As Immunogenic Responsesmentioning

confidence: 99%

“…This in turn is associated with an improved induction of MHC class I–restricted HSV‐1‐specific antiviral immunity, dependent on TLR3 signaling. [ 12 ] NF‐κB also appears to be important for human LC activation through TLR2 signaling, resulting in up‐regulation of CD86, CD83, CCR7, TNF and IL‐6, and the priming of CD4 T cell responses. [ 95 ]…”

Section: Lc Immunogenicity Is Promoted By the Transcription Factors Irf1 And Nfkbmentioning

confidence: 99%

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Tolerogenic and immunogenic states of Langerhans cells are orchestrated by epidermal signals acting on a core maturation gene module

Polak

Singh

2021

BioEssays

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Langerhans cells (LCs), residing in the epidermis, are able to induce potent immunogenic responses and also to mediate immune tolerance. We propose that tolerogenic and immunogenic responses of LCs are directed by signaling from the epidermis and involve counter-acting gene circuits that are coupled to a core maturation gene module. We base our analysis on recent genetic and genomic findings facilitating the understanding of the molecular mechanisms controlling these divergent immune functions. Comparing gene regulatory network (GRN) analyses of various types of dendritic cells (DCs) including LCs we integrate signaling-dependent (TGFβ, EpCAM, β-Catenin) and transcription factor (IRF4, IRF1, NFκB) regulated gene circuits that appear to orchestrate the distinctive LC functional states. Our model proposes, that while epidermal signaling in the steady-state promotes LC tolerogenic function, the disruption of cellcell contacts coupled with inflammatory signaling induces LC immunogenic programing. The conceptual framework emphasizes the sensing of discrete epidermal and inflammatory cues by resident LCs in dictating their genomic programing and cell state dynamics.

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“…RANKL:RANK engagement prevents LC apoptosis, and enhances LC migration to regional lymph nodes. This is associated with an improved induction of MHC class I-restricted HSV-1-specific antiviral immunity, dependent on TLR3 signaling ( 90 ). We and others have shown that LCs are equipped with a range of surface receptors, including pattern recognition receptors, pathogen uptake-receptors (Langerin and DEC205) as well as intracellular sensors of microenvironmental changes, such as caveolin (CAV1) and endosulfine alpha ( 12 , 60 , 91 – 95 ).…”

Section: Nf-κb Systemmentioning

confidence: 99%

Langerhans Cells—Programmed by the Epidermis

et al. 2017

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Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels. These cells determine the appropriate adaptive immune response (inflammation or tolerance) by interpreting the microenvironmental context in which they encounter foreign substances. In a normal physiological, “non-dangerous” situation, LCs coordinate a continuous state of immune tolerance, preventing unnecessary and harmful immune activation. Conversely, when they sense a danger signal, for example during infection or when the physical integrity of skin has been compromised as a result of a trauma, they instruct T lymphocytes of the adaptive immune system to mount efficient effector responses. Recent advances investigating the molecular mechanisms underpinning the cross talk between LCs and the epidermal microenvironment reveal its importance for programming LC biology. This review summarizes the novel findings describing LC origin and function through the analysis of the transcriptomic programs and gene regulatory networks (GRNs). Review and meta-analysis of publicly available datasets clearly delineates LCs as distinct from both conventional dendritic cells (DCs) and macrophages, suggesting a primary role for the epidermal microenvironment in programming LC biology. This concept is further supported by the analysis of the effect of epidermal pro-inflammatory signals, regulating key GRNs in human and murine LCs. Applying whole transcriptome analyses and in silico analysis has advanced our understanding of how LCs receive, integrate, and process signals from the steady-state and diseased epidermis. Interestingly, in homeostasis and under immunological stress, the molecular network in LCs remains relatively stable, reflecting a key evolutionary need related to tissue localization. Importantly, to fulfill their key role in orchestrating antiviral adaptive immune responses, LC share specific transcriptomic modules with other DC types able to cross-present antigens to cytotoxic CD8+ T cells, pointing to a possible evolutionary convergence mechanism. With the development of more advanced technologies allowing delineation of the molecular networks at the level of chromatin organization, histone modifications, protein translation, and phosphorylation, future “omics” investigations will bring in-depth understanding of the complex molecular mechanisms underpinning human LC biology.

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Cutaneous RANK–RANKL Signaling Upregulates CD8-Mediated Antiviral Immunity during Herpes simplex Virus Infection by Preventing Virus-Induced Langerhans Cell Apoptosis

Cited by 10 publications

References 45 publications

Eimeria challenge adversely affected long bone attributes linked to increased resorption in 14-day-old broiler chickens

Eimeria challenge adversely affected long bone attributes linked to increased resorption in 14-day-old broiler chickens

Tolerogenic and immunogenic states of Langerhans cells are orchestrated by epidermal signals acting on a core maturation gene module

Langerhans Cells—Programmed by the Epidermis

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