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Cell Apr 2021Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal...
Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.
Topics: Animals; Cells, Cultured; Dermatitis; Diphtheria Toxin; Disease Models, Animal; Female; Glutamic Acid; Integrin beta Chains; Langerhans Cells; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Receptors, G-Protein-Coupled; Skin; beta-Alanine
PubMed: 33765440
DOI: 10.1016/j.cell.2021.03.002 -
Immunity Oct 2021Langerhans cells (LCs) play a pivotal role in skin homeostasis, and the heterogeneity of LCs has long been considered. In this study, we have identified two steady-state...
Langerhans cells (LCs) play a pivotal role in skin homeostasis, and the heterogeneity of LCs has long been considered. In this study, we have identified two steady-state (LC1 and LC2) and two activated LC subsets in the epidermis of human skin and in LCs derived from CD34 hemopoietic stem cells (HSC-LCs) by utilizing single-cell RNA sequencing and mass cytometry. Analysis of HSC-LCs at multiple time-points during differentiation revealed that EGR1 and Notch signaling were among the top pathways regulating the bifurcation of LC1 and LC2. LC1 were characterized as classical LCs, mainly related to innate immunity and antigen processing. LC2 were similar to monocytes or myeloid dendritic cells, involving in immune responses and leukocyte activation. LC1 remained stable under inflammatory microenvironment, whereas LC2 were prone to being activated and demonstrated elevated expression of immuno-suppressive molecules. We revealed distinct human LC subsets that require different developmental regulation and orchestrate reciprocal functions.
Topics: Antigen Presentation; Cell Differentiation; Hematopoietic Stem Cells; Humans; Immunity, Innate; Langerhans Cells; Skin
PubMed: 34508661
DOI: 10.1016/j.immuni.2021.08.012 -
Cell Communication and Signaling : CCS Aug 2018The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual's... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual's health conditions. For example, we believe that the pathogenetic potential of the Merkel cell polyomavirus (MCPyV), the resident virus in skin, is variable and depends from the degree of individual's reactivity. MCPyV as well as Epstein-Barr virus, which are normally connected with humans under the form of subclinical infection, are thought to be involved at various degrees in several neoplastic and inflammatory diseases. In this review, we cover two types of Langerhans cell neoplasms, the Langerhans cell sarcoma (LCS) and Langerhans cell histiocytosis (LCH), represented as either neoplastic or inflammatory diseases caused by MCPyV.
METHODS
We meta-analyzed both our previous analyses, composed of quantitative PCR for MCPyV-DNA, proteomics, immunohistochemistry which construct IL-17 endocrine model and interleukin-1 (IL-1) activation loop model, and other groups' data.
RESULTS
We have shown that there were subgroups associated with the MCPyV as a causal agent in these two different neoplasms. Comparatively, LCS, distinct from the LCH, is a neoplastic lesion (or sarcoma) without presence of inflammatory granuloma frequently observed in the elderly. LCH is a proliferative disease of Langerhans-like abnormal cells which carry mutations of genes involved in the RAS/MAPK signaling pathway. We found that MCPyV may be involved in the development of LCH.
CONCLUSION
We hypothesized that a subgroup of LCS developed according the same mechanism involved in Merkel cell carcinoma pathogenesis. We proposed LCH developed from an inflammatory process that was sustained due to gene mutations. We hypothesized that MCPyV infection triggered an IL-1 activation loop that lies beneath the pathogenesis of LCH and propose a new triple-factor model.
Topics: Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Merkel cell polyomavirus; Models, Biological; Sarcoma
PubMed: 30134914
DOI: 10.1186/s12964-018-0261-y -
Current Opinion in Hematology Jan 2016This article summarizes recent research on the ontogeny of Langerhans cells and regulation of their homeostasis in quiescent and inflamed conditions. (Review)
Review
PURPOSE OF REVIEW
This article summarizes recent research on the ontogeny of Langerhans cells and regulation of their homeostasis in quiescent and inflamed conditions.
RECENT FINDINGS
Langerhans cells originate prenatally and may endure throughout life, independently of bone marrow-derived precursors. Fate-mapping experiments have recently resolved the relative contribution of primitive yolk sac and fetal liver hematopoiesis to the initial formation of Langerhans cells. In postnatal life, local self-renewal restores Langerhans cell numbers following chronic or low-grade inflammatory insults. However, severe inflammation recruits de-novo bone marrow-derived precursors in two waves; a transient population of classical monocytes followed by uncharacterized myeloid precursors that form a stable self-renewing Langerhans cell network as inflammation subsides. Human CD1c⁺ dendritic cells have Langerhans cell potential in vitro, raising the possibility that dendritic cell progenitors provide the second wave. Langerhans cell development depends upon transforming growth factor beta receptor signaling with distinct pathways active during differentiation and homeostasis. Langerhans cell survival is mediated by multiple pathways including mechanistic target of rapamycin and extracellular signal-regulated kinase signaling, mechanisms that become highly relevant in Langerhans cell neoplasia.
SUMMARY
The study of Langerhans cells continues to provide novel and unexpected insights into the origin and regulation of myeloid cell populations. The melding of macrophage and dendritic cell biology, shaped by a unique habitat, is a special feature of Langerhans cells.
Topics: Animals; Cell Differentiation; Cell Lineage; Cell Self Renewal; Fetus; Histiocytosis, Langerhans-Cell; Homeostasis; Humans; Inflammation; Langerhans Cells; Liver; Macrophages; Monocytes; Stem Cells; Yolk Sac
PubMed: 26554892
DOI: 10.1097/MOH.0000000000000202 -
Nihon Rinsho Men'eki Gakkai Kaishi =... 2011Heterosexual transmission of HIV is the most common mode of infection in the global HIV epidemic. In the absence of an effective vaccine, there is an urgent need for... (Review)
Review
Heterosexual transmission of HIV is the most common mode of infection in the global HIV epidemic. In the absence of an effective vaccine, there is an urgent need for additional strategies to prevent new HIV infections. Evidence from a variety of investigations, including epidemiologic studies on sexual transmission, in vivo studies in rhesus monkey, and ex vivo studies using human explant models, indicate that CD4/CCR5-mediated de novo infection of Langerhans cells (LCs) is a major pathway involved in sexual transmission of HIV (LCs primary gate keeper model). However, it has been recently revealed that Langerin (a C-type lectin receptor) expressed on LC inactivate HIV. Thus, there may be multiple ways by which HIV interacts with LCs in the genital mucosa. In light of the current HIV infection rates in heterosexuals and the absence of a prophylactic vaccine, prevention strategies, such as topical microbicides that block sexual transmission of HIV, are urgently needed. This review focuses on the recent advances regarding the role of LCs in heterosexual transmission of HIV, and the relationship between the LCs primary gate keeper model and current prevention strategies worldwide.
Topics: Animals; Anti-Infective Agents; CD4 Antigens; Circumcision, Male; Drug Design; Female; HIV; HIV Infections; Humans; Langerhans Cells; Male; Receptors, CCR5; Skin
PubMed: 21628848
DOI: 10.2177/jsci.34.70 -
Oncology (Williston Park, N.Y.) Feb 2016Langerhans cell histiocytosis is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate. Langerhans cell... (Review)
Review
Langerhans cell histiocytosis is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate. Langerhans cell histiocytosis has a highly variable clinical presentation, ranging from a single lesion to potentially fatal disseminated disease. The uncertainty as to whether Langerhans cell histiocytosis is a reactive or a neoplastic disease has resulted in a long-standing debate on this question, and the limited understanding of the pathogenesis of the disease has impeded clinical improvement for patients. The current standard of care for multisystem Langerhans cell histiocytosis, empirically derived chemotherapy with vinblastine and prednisone, cures fewer than 50% of patients, and optimal therapies for relapse and neurodegenerative disease remain uncertain. Recent research advances support a model in which Langerhans cell histiocytosis arises due to pathologic activation of the mitogen-activated protein kinase (MAPK) pathway in myeloid precursors. Redefinition of Langerhans cell histiocytosis as a myeloid neoplastic disorder driven by hyperactive ERK supports the potential of chemotherapy with efficacy against immature myeloid cells, as well as mutation-specific targeted therapy.
Topics: Animals; Antigens, CD; Disease Progression; Enzyme Activation; Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Lectins, C-Type; Mannose-Binding Lectins; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Prednisone; Protein Kinase Inhibitors; Signal Transduction; Treatment Outcome; Vinblastine
PubMed: 26888790
DOI: No ID Found -
Journal of Anatomy Aug 2019Skin Langerhans cells are antigen-presenting cells of the interfollicular epidermis and the upper part of the hair follicle, whereas osteoclasts are specialized... (Comparative Study)
Comparative Study Review
Skin Langerhans cells are antigen-presenting cells of the interfollicular epidermis and the upper part of the hair follicle, whereas osteoclasts are specialized bone-resorbing macrophages. Although at first view these two cell types appear to have little in common, a closer analysis reveals shared features, and when taking into account their surrounding environment, a hypothesis can be developed that Langerhans cells and osteoclasts have evolved from a common ancestral cell type. In this mini-review, we have compared the ontogenetic features of Langerhans cells and osteoclasts from a genetic and a functional point of view, an issue that so far has been overlooked. The gene programs that control cell differentiation, and the body parts where they reside, present surprising similarities. Whereas the function of osteoclasts in bone degradation has been established since the first vertebrates, Langerhans cells may have undergone a stepwise adaptation from aquatic to terrestrial life. Their cell function co-evolved with the imperatives of the skin to protect against physical impact, heat, water loss and pathogens, which implied the capacity of Langerhans cells to associate with skin appendages and to develop immunostimulatory functions. For the highly versatile and efficient immune system of modern vertebrates, Langerhans cells may be a memory of the past.
Topics: Animals; Biological Evolution; Humans; Langerhans Cells; Osteoclasts
PubMed: 27620531
DOI: 10.1111/joa.12543 -
Pflugers Archiv : European Journal of... Apr 2017The skin and its appendages comprise the largest and fastest growing organ in the body. It performs multiple tasks and maintains homeostatic control, including the... (Review)
Review
The skin and its appendages comprise the largest and fastest growing organ in the body. It performs multiple tasks and maintains homeostatic control, including the regulation of body temperature and protection from desiccation and from pathogen invasion. The skin can perform its functions with the assistance of different immune cell populations. Monocyte-derived cells are imperative for the completion of these tasks. The comprehensive role of macrophages and Langerhans cells in establishing and maintaining skin homeostasis remains incompletely defined. However, over the past decade, innovations in mouse genetics have allowed for advancements in the field. In this review, we explore different homeostatic roles of macrophages and Langerhans cells, including wound repair, follicle regeneration, salt balance, and cancer regression and progression in the skin. The understanding of the precise functions of myeloid-derived cells in the skin under basal conditions can help develop specific therapies that aid in skin and hair follicle regeneration and cutaneous cancer prevention.
Topics: Animals; Homeostasis; Humans; Langerhans Cells; Macrophages; Skin; Wound Healing
PubMed: 28233123
DOI: 10.1007/s00424-017-1953-7 -
Blood Nov 1994The term histiocyte refers to cells of either the macrophage or Langerhans cell lineages. The histiocytic disorders are characterized by the proliferation of cells of... (Review)
Review
The term histiocyte refers to cells of either the macrophage or Langerhans cell lineages. The histiocytic disorders are characterized by the proliferation of cells of these lineages. With recent advances in knowledge of the developmental biology of histiocytic cells, it is now possible to formulate a reasonable catalogue of histiocytic diseases based on ultra-structural and phenotypic markers of cellular origins and molecular or chromosomal markers of malignancy. The catalogue includes the following groups of diseases. Nonmalignant reactive macrophage disorders include (1) macrophage storage diseases, (2) several benign proliferative macrophage disorders that predominantly involve skin and bone, and (3) several hemophagocytic syndromes that vary from indolent and benign to fulminant and fatal. In some of the latter disorders, viruses have been identified as the inciting stimulus. The malignant macrophage disorders include (1) acute monocytic leukemia and (2) chronic myelomonocytic leukemia. A rare disorder that gave rise to a permanent cell line with an anomaly of chromosomal segment 5q35 may also be an example of a histiocytic malignancy. The existence of a separate category of true histiocytic lymphoma of macrophage type is uncertain. Reactive Langerhans cell disorders include (1) congenital self-healing histiocytosis, (2) the many variants of eosinophilic granuloma, and (3) a related disorder designated as relapsing Langerhans cell histiocytosis that is characterized by a relapsing course and infiltration of bone and soft tissues by Langerhans cells. Presumptively neoplastic diseases of Langerhans and dendritic cells include (1) progressive Langerhans cell histiocytosis, a disease with prominent involvement of blood and BM as well as skin and viscera; (2) Langerhans cell lymphoma, and (3) dendritic cell lymphoma. However, clonality as a marker of malignancy has not been proven in these disorders.
Topics: Antigens, CD; Antigens, CD34; Biomarkers; Cell Differentiation; Dendritic Cells; Hematopoietic Stem Cells; Histiocytes; Histiocytosis; Humans; Langerhans Cells
PubMed: 7524755
DOI: No ID Found -
Orphanet Journal of Rare Diseases Mar 2012Pulmonary Langerhans Cell Histiocytosis (PLCH) is a relatively uncommon lung disease that generally, but not invariably, occurs in cigarette smokers. The pathologic... (Review)
Review
Pulmonary Langerhans Cell Histiocytosis (PLCH) is a relatively uncommon lung disease that generally, but not invariably, occurs in cigarette smokers. The pathologic hallmark of PLCH is the accumulation of Langerhans and other inflammatory cells in small airways, resulting in the formation of nodular inflammatory lesions. While the overwhelming majority of patients are smokers, mechanisms by which smoking induces this disease are not known, but likely involve a combination of events resulting in enhanced recruitment and activation of Langerhans cells in small airways. Bronchiolar inflammation may be accompanied by variable lung interstitial and vascular involvement. While cellular inflammation is prominent in early disease, more advanced stages are characterized by cystic lung destruction, cicatricial scarring of airways, and pulmonary vascular remodeling. Pulmonary function is frequently abnormal at presentation. Imaging of the chest with high resolution chest CT scanning may show characteristic nodular and cystic abnormalities. Lung biopsy is necessary for a definitive diagnosis, although may not be required in instances were imaging findings are highly characteristic. There is no general consensus regarding the role of immunosuppressive therapy in smokers with PLCH. All smokers must be counseled on the importance of smoking cessation, which may result in regression of disease and obviate the need for systemic immunosuppressive therapy. The prognosis for most patients is relatively good, particularly if longitudinal lung function testing shows stability. Complications like pneumothoraces and secondary pulmonary hypertension may shorten life expectancy. Patients with progressive disease may require lung transplantation.
Topics: Adult; Child, Preschool; Female; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Infant; Langerhans Cells; Lung Diseases; Male; Pneumothorax; Prognosis; Respiratory Function Tests; Smoking; Young Adult
PubMed: 22429393
DOI: 10.1186/1750-1172-7-16