MRGPR-mediated activation of local mast cells clears cutaneous bacterial infection and protects against reinfection

Mast cells (MCs) are strategically distributed at barrier sites and prestore various immunocyte-recruiting cytokines, making them ideal targets for selective activation to treat peripheral infections. Here, we report that topical treatment with mastoparan, a peptide MC activator (MCA), enhances clearance ofStaphylococcus aureusfrom infected mouse skins and accelerates healing of dermonecrotic lesions. Mastoparan functions by activating connective tissue MCs (CTMCs) via the MRGPRX2 (Mas-related G protein-coupled receptor member X2) receptor. Peripheral CTMC activation, in turn, enhances recruitment of bacteria-clearing neutrophils and wound-healing CD301b+dendritic cells. Consistent with MCs playing a master coordinating role, MC activation also augmented migration of various antigen-presenting dendritic cells to draining lymph nodes, leading to stronger protection against a second infection challenge. MCAs therefore orchestrate both the innate and adaptive immune arms, which could potentially be applied to combat peripheral infections by a broad range of pathogens.

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Effects of Staphylococcus aureus Bacteriophage K on Expression of Cytokines and Activation Markers by Human Dendritic Cells In Vitro

Viruses ◽

10.3390/v10110617 ◽

2018 ◽

Vol 10 (11) ◽

pp. 617 ◽

Cited By ~ 5

Author(s):

Helen Freyberger ◽

Yunxiu He ◽

Amanda Roth ◽

Mikeljon Nikolich ◽

Andrey Filippov

Keyword(s):

Staphylococcus Aureus ◽

Dendritic Cells ◽

Inflammatory Response ◽

Adaptive Immune Response ◽

Human Monocyte ◽

Activation Markers ◽

Mhc I ◽

Adaptive Immune ◽

Human Dendritic Cells

A potential concern with bacteriophage (phage) therapeutics is a host-versus-phage response in which the immune system may neutralize or destroy phage particles and thus impair therapeutic efficacy, or a strong inflammatory response to repeated phage exposure might endanger the patient. Current literature is discrepant with regard to the nature and magnitude of innate and adaptive immune response to phages. The purpose of this work was to study the potential effects of Staphylococcus aureus phage K on the activation of human monocyte-derived dendritic cells. Since phage K acquired from ATCC was isolated around 90 years ago, we first tested its activity against a panel of 36 diverse S. aureus clinical isolates from military patients and found that it was lytic against 30/36 (83%) of strains. Human monocyte-derived dendritic cells were used to test for an in vitro phage-specific inflammatory response. Repeated experiments demonstrated that phage K had little impact on the expression of pro- and anti-inflammatory cytokines, or on MHC-I/II and CD80/CD86 protein expression. Given that dendritic cells are potent antigen-presenting cells and messengers between the innate and the adaptive immune systems, our results suggest that phage K does not independently affect cellular immunity or has a very limited impact on it.

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Staphylococcus aureusImpairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin

mBio ◽

10.1128/mbio.01918-18 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 12

Author(s):

Evelien T. M. Berends ◽

Xuhui Zheng ◽

Erin E. Zwack ◽

Mickaël M. Ménager ◽

Michael Cammer ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Dendritic Cells ◽

Adaptive Immunity ◽

T Cell Activation ◽

Antigen Presenting Cells ◽

Infection Model ◽

High Morbidity ◽

Content Type ◽

Human Dendritic Cells ◽

Antigen Presenting

ABSTRACTStaphylococcus aureusis a human pathogen responsible for high morbidity and mortality worldwide. Recurrent infections with this bacterium are common, suggesting thatS. aureusthwarts the development of sterilizing immunity.S. aureusstrains that cause disease in humans produce up to five different bicomponent toxins (leukocidins) that target and lyse neutrophils, innate immune cells that represent the first line of defense againstS. aureusinfections. However, little is known about the role of leukocidins in blunting adaptive immunity. Here, we explored the effects of leukocidins on human dendritic cells (DCs), antigen-presenting cells required for the development of adaptive immunity. Using anex vivoinfection model of primary human monocyte-derived dendritic cells, we found thatS. aureus, including strains from different clonal complexes and drug resistance profiles, effectively kills DCs despite efficient phagocytosis. Although all purified leukocidins could kill DCs, infections with live bacteria revealed thatS. aureustargets and kills DCs primarily via the activity of leukocidin LukAB. Moreover, using coculture experiments performed with DCs and autologous CD4+T lymphocytes, we found that LukAB inhibits DC-mediated activation and proliferation of primary human T cells. Taken together, the data determined in the study reveal a novel immunosuppressive strategy ofS. aureuswhereby the bacterium blunts the development of adaptive immunity via LukAB-mediated injury of DCs.IMPORTANCEAntigen-presenting cells such as dendritic cells (DCs) fulfill an indispensable role in the development of adaptive immunity by producing proinflammatory cytokines and presenting microbial antigens to lymphocytes to trigger a faster, specific, and long-lasting immune response. Here, we studied the effect ofStaphylococcus aureustoxins on human DCs. We discovered that the leukocidin LukAB hinders the development of adaptive immunity by targeting human DCs. The ability ofS. aureusto blunt the function of DCs could help explain the high frequency of recurrentS. aureusinfections. Taken together, the results from this study suggest that therapeutically targeting theS. aureusleukocidins may boost effective innate and adaptive immune responses by protecting innate leukocytes, enabling proper antigen presentation and T cell activation.

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Understanding Dendritic Cells and Their Role in Cutaneous Carcinoma and Cancer Immunotherapy

Clinical and Developmental Immunology ◽

10.1155/2013/624123 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 22

Author(s):

Valerie R. Yanofsky ◽

Hiroshi Mitsui ◽

Diane Felsen ◽

John A. Carucci

Keyword(s):

Dendritic Cells ◽

Complex Nature ◽

Adaptive Immune ◽

Depth Analysis ◽

New Strategy ◽

Antigen Presenting ◽

Cancer Immunotherapies ◽

Adaptive Immune Systems ◽

Epidermal Langerhans Cells ◽

The Ideal

Dendritic cells (DC) represent a diverse group of professional antigen-presenting cells that serve to link the innate and adaptive immune systems. Their capacity to initiate a robust and antigen-specific immune response has made them the ideal candidates for cancer immunotherapies. To date, the clinical impact of DC immunotherapy has been limited, which may, in part, be explained by the complex nature of DC biology. Multiple distinct subsets of DCs have been identified in the skin, where they can be broadly subcategorized into epidermal Langerhans cells (LC), myeloid-derived dermal dendritic cells (mDC) and plasmacytoid dendritic cells (pDC). Each subset is functionally unique and may activate alternate branches of the immune system. This may be relevant for the treatment of squamous cell carcinoma, where we have shown that the tumor microenvironment may preferentially suppress the activity of mDCs, while LCs remain potent stimulators of immunity. Here, we provide an in depth analysis of DC biology, with a particular focus on skin DCs and their role in cutaneous carcinoma. We further explore the current approaches to DC immunotherapy and provide evidence for the targeting of LCs as a promising new strategy in the treatment of skin cancer.

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Chemokines and dendritic cells in inflammatory myopathies: Figure 1

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.095984 ◽

2009 ◽

Vol 68 (3) ◽

pp. 300-304 ◽

Cited By ~ 13

Author(s):

A Tournadre ◽

P Miossec

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Inflammatory Diseases ◽

Inflammatory Cells ◽

Inflammatory Myopathies ◽

T Helper ◽

Adaptive Immune ◽

Antigen Presenting ◽

Leucocyte Recruitment

This review focuses on the contribution of the local production of chemokines and cytokines and of dendritic cells (DC) to the pathogenesis of inflammatory myopathies. DC are the most efficient professional antigen-presenting cells (APC), which are critical for the development of innate and adaptive immune responses. Chemokines are important mediators of the immune response as they regulate leucocyte recruitment to tissue and play a key role in inflammatory diseases by acting on T-cell and DC migration. Recent advances indicate that the muscle cell itself could participate in the inflammatory process. Furthermore, the T-helper (Th) type 1 and Th17 proinflammatory cytokines, present in myositis samples, are associated with the migration, differentiation and maturation of inflammatory cells and allow a network of interactions between all the components of the immune response. An understanding of such interactions is essential because it can lead to therapeutic applications.

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Dendritic cells and T cells in rheumatoid arthritis

Oxford Textbook of Rheumatoid Arthritis ◽

10.1093/med/9780198831433.003.0008 ◽

2020 ◽

pp. 73-84

Author(s):

Soi-Cheng Law ◽

Pascale Wehr ◽

Harriet Purvis ◽

Ranjeny Thomas

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Dendritic Cells ◽

Autoimmune Response ◽

Immune Effector ◽

Effector Functions ◽

Adaptive Immune ◽

Cell Antibody ◽

Innate Immune Effector ◽

Antigen Presenting

Dendritic cells (DCs) are specialized antigen-presenting cells which link the innate and adaptive immune responses, activating and priming effector CD4+ T cells, cross-presenting antigen to CD8+ T cells, and promoting B-cell antibody production. DCs also play important roles in the maintenance of immune tolerance. DCs and T cells underpin the basis of the autoimmune response in rheumatoid arthritis. In this chapter we describe the function of DCs and the response of T cells in rheumatoid arthritis pathogenesis, introduce the DC and T-cell players and their function in the immune system, then review the evidence for their involvement in the pathogenesis of rheumatoid arthritis (RA), particularly through the presentation of antigen that triggers the differentiation of autoreactive T cells, as well as innate immune effector functions. Finally, the emerging prospects for DC targeting for immunotherapy are covered.

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Dendritic cells and isolevuglandins in immunity, inflammation, and hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00603.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. H368-H374 ◽

Cited By ~ 24

Author(s):

Kala B. Dixon ◽

Sean S. Davies ◽

Annet Kirabo

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Protein Modification ◽

Vascular Dysfunction ◽

Organ Damage ◽

Activated T Cells ◽

Adaptive Immune ◽

The Past ◽

Antigen Presenting

Hypertension is the major risk factor for morbidity and mortality from myocardial infarction, stroke, heart failure, and chronic kidney disease. Despite its importance, the pathogenesis of essential hypertension is poorly understood. During the past several years, it has become evident that T cells contribute to hypertension. Activated T cells accumulate in the perivascular space and the kidney and release cytokines that promote vascular dysfunction and end-organ damage. Although dendritic cells play a pivotal role in initiating adaptive immune responses, T cells have taken center stage in studies implicating the immune system in the genesis of hypertension. The mechanisms by which T cells are activated and the antigens involved are poorly understood. We recently showed that hypertension is associated with increased dendritic cell production of the TH17 polarizing cytokines, IL-6, IL-1β, and IL-23. This occurs in part by increased superoxide production via NADPH oxidase and protein modification by highly reactive isolevuglandins (IsoLGs). IsoLGs are produced via the isoprostane pathway of free radical-mediated lipid peroxidation and, when adducted to proteins, have the potential to act as neoantigens. In this review, we discuss recent advances in our understanding of the role of antigen-presenting dendritic cells in the pathophysiology of hypertension and highlight potential neoantigens that may contribute to this disease.

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Mast cells acquire MHCII from dendritic cells during skin inflammation

Journal of Experimental Medicine ◽

10.1084/jem.20160783 ◽

2017 ◽

Vol 214 (12) ◽

pp. 3791-3811 ◽

Cited By ~ 24

Author(s):

Jan Dudeck ◽

Anna Medyukhina ◽

Julia Fröbel ◽

Carl-Magnus Svensson ◽

Johanna Kotrba ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Mast Cells ◽

Ex Vivo ◽

Multiphoton Microscopy ◽

Skin Inflammation ◽

Critical Periods ◽

Reporter Mice ◽

Antigen Presenting

Mast cells (MCs) and dendritic cells (DCs) are essential innate sentinels populating host-environment interfaces. Using longitudinal intravital multiphoton microscopy of DCGFP/MCRFP reporter mice, we herein provide in vivo evidence that migratory DCs execute targeted cell-to-cell interactions with stationary MCs before leaving the inflamed skin to draining lymph nodes. During initial stages of skin inflammation, DCs dynamically scan MCs, whereas at a later stage, long-lasting interactions predominate. These innate-to-innate synapse-like contacts ultimately culminate in DC-to-MC molecule transfers including major histocompatibility complex class II (MHCII) proteins enabling subsequent ex vivo priming of allogeneic T cells with a specific cytokine signature. The extent of MHCII transfer to MCs correlates with their T cell priming efficiency. Importantly, preventing the cross talk by preceding DC depletion decreases MC antigen presenting capacity and T cell–driven inflammation. Consequently, we identify an innate intercellular communication arming resident MCs with key DC functions that might contribute to the acute defense potential during critical periods of migration-based DC absence.

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FC-98 Regulates TLR9-Mediated of CXCL-10 Expression in Dendritic Cells via MAPK and STAT1 Signaling Pathway

BioMed Research International ◽

10.1155/2014/926130 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Yonghong Yang ◽

Huan Dou ◽

Xiaoqin Li ◽

Yuxian Song ◽

Wei Gong ◽

...

Keyword(s):

Dendritic Cells ◽

Surface Markers ◽

Toll Like Receptor ◽

Cpg Dna ◽

Bacterial Dna ◽

Adaptive Immune ◽

Stat1 Signaling ◽

And Function ◽

Antigen Presenting ◽

Adaptive Immune Systems

Dendritic cells (DCs), as the most potent professional antigen presenting cells, play a crucial role in both innate and adaptive immune systems. Genomic bacterial DNA mimicked by unmethylated CpG motifs is discovered to possess immunostimulatory effects. CpG-DNA recognized by Toll-like receptor 9 (TLR9) on DCs arouses many immune diseases (such as cancer, viral infection, and autoimmune disorders). In this study we investigated the effects of FC-98 on CpG-induced bone marrow-derived DCs (BMDCs). The results showed that FC-98 significantly inhibited the CpG-induced BMDCs maturation and function by suppressing the expression of surface markers (CD40, CD80, CD86, and MHCII). Moreover, FC-98 downregulated the expression of C-X-C motif chemokine 10 (CXCL-10) both at the mRNA and protein level after CpG induction. Meanwhile, FC-98 markedly affected the migration of BMDCs to T cells without affecting their endocytosis capacity. Furthermore, FC-98 was confirmed to decrease CXCL-10 expression by inhibiting CpG-induced activation of MAPKs (ERK, JNK, and p38) and STAT1 signaling. Overall, these results suggested that FC-98 was a potential molecule in the treatment of CXCL-10-mediated immune diseases.

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Regulation of Murine Dendritic Cell Immune Responses by Helicobacter felis Antigen

Infection and Immunity ◽

10.1128/iai.00289-06 ◽

2006 ◽

Vol 74 (8) ◽

pp. 4624-4633 ◽

Cited By ~ 18

Author(s):

Maureen L. Drakes ◽

Steven J. Czinn ◽

Thomas G. Blanchard

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Dendritic Cell ◽

Immune Responses ◽

Lamina Propria ◽

Adaptive Immune Responses ◽

Helicobacter Felis ◽

Adaptive Immune ◽

Pulsed Dc ◽

Antigen Presenting

ABSTRACT Helicobacter infections are present in approximately 50% of humans, causing severe illnesses such as gastritis and malignancies. Dendritic cells (DC) are critical antigen-presenting cells which link innate and adaptive immune responses. The mechanism of dendritic cell regulation in Helicobacter-induced gastritis is poorly understood. These studies characterized DC isolated from the lamina propria of Helicobacter-infected mice and analyzed innate and adaptive immune responses elicited by Helicobacter antigen (Ag)-pulsed DC. The presence of DC was elevated in the gastric lamina propria infiltrate of infected mice in comparison with controls. After treatment with Helicobacter felis Ag, DC were polarized to secrete interleukin-6 as the dominant cytokine. In the presence of DC and Helicobacter Ag, responder allogeneic T cells in culture exhibited limited cell division. We suggest that the response of DC and T cells to Helicobacter Ag is critical to the chronic persistence of Helicobacter-induced gastritis.

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Leptin’s and antigen-presenting cells’ functions in periodontitis – an overview / Leptin e as funções das células que apresentam antigénios na periodontite - uma visão geral

Brazilian Journal of Health Review ◽

10.34119/bjhrv4n2-333 ◽

2021 ◽

Vol 4 (2) ◽

pp. 8011-8019

Author(s):

Giovanna Ganem Favero ◽

Isabela Lopes Martin ◽

Fernanda Pereira da Silva Albino ◽

Carlos Eduardo Fontana ◽

Sérgio Luiz Pinheiro ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Immune Responses ◽

Inflammatory Responses ◽

Antigen Presenting Cells ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Inflammatory Immune Response ◽

Antigen Presenting ◽

The Relationship

Leptin is a hormone synthesized predominantly by white adipose tissue. Its production levels are directly proportional to the total mass of this tissue in an individual’s body. Apart from its classic role in the regulation of hunger and satiety, it also plays an important part in scenarios involving innate and adaptive immune responses. It has been discovered that leptin levels are altered in a variety of inflammatory responses, such as periodontitis, a condition which derives from a persistent inflammatory immune response from a host facing bacterial infection. The initial trigger for this reaction is the recognition of the pathogens by antigen presenting cells, such as macrophages and dendritic cells, whose actions can be influenced by leptin. This review aims to present the relationship between leptin, dendritic cells and macrophages in the context of periodontal disease. Thus, we have assembled the most important findings related to leptin’s role in the modulation of the immune response carried out by these cells in periodontitis.

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