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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 47357

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Special Issue Editor

Dr. Marcello Chieppa

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Guest Editor

National Institute of Gastroenterology “S. de Bellis”, Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy
Interests: dendritic cells; mucosal immunology; inflammation; innate immunity; inflammatory bowel disease (IBD); nutrition
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Dear Colleagues,

In 1973, a new type of cell was described. These cells, only partially resembling macrophages, were characterized by dendrite-like projections and for this reason they were named dendritic cells (DCs). The first functional analysis revealed them as the most potent antigen-presenting cells, able to capture, process, and present antigens to initiate the adaptive immune response. Soon after, Steinman was beginning to understand that the role of DCs was not only related with the initiation of the aggressive immune response, but also with the immunological tolerance: “The function of these presenting cells in immunologic tolerance is just beginning to be studied.”

It is now clear that DCs’ biology and response is extremely diverse, as results of the DC subpopulation considered, the tissue analyzed, and even the same subpopulation in the same tissue could act differently in response to environmental factors.

With the present Special Issue, we aim to elucidate DCs’ role during inflammation, host defense, inflammatory suppression, and potential contribution to dysregulated immune response leading to chronic inflammatory syndromes.

DCs could be biological targets of future precision therapies, but the complex biology of these cells requires detailed knowledge of their biology. This Special Issue will consider reviews and original manuscripts that highlight DCs’ response in extreme conditions: chronic inflammation, infection, auto-immune response, and undesired induction of tolerance.

Dr. Marcello Chieppa
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

dendritic cells
immunological tolerance
chronic inflammation
infection
auto-immune response

Published Papers (11 papers)

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Editorial

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2 pages, 177 KiB

Open AccessEditorial

Role of Dendritic Cells in Inflammation

by Marcello Chieppa

Int. J. Mol. Sci. 2020, 21(12), 4432; https://doi.org/10.3390/ijms21124432 - 22 Jun 2020

Viewed by 1571

Abstract

From the first manuscript describing “A Novel Cell Type in Peripheral Lymphoid Organs of Mice” [...] Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

Research

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11 pages, 2973 KiB

Open AccessArticle

Iron Overload Mimicking Conditions Skews Bone Marrow Dendritic Cells Differentiation into MHCII^lowCD11c⁺CD11b⁺F4/80⁺ Cells

by Giulio Verna, Marina Liso, Stefania De Santis, Manuela Dicarlo, Elisabetta Cavalcanti, Alberto Crovace, Annamaria Sila, Pietro Campiglia, Angelo Santino, Antonio Lippolis, Grazia Serino, Alessio Fasano and Marcello Chieppa

Int. J. Mol. Sci. 2020, 21(4), 1353; https://doi.org/10.3390/ijms21041353 - 17 Feb 2020

Cited by 7 | Viewed by 3224

Abstract

Iron overload is an undesired effect of frequent blood transfusions or genetic diseases. Myelodysplastic syndrome (MDS) patients become transfusion dependent, but due to the combination of ineffective haematopoiesis and repeated blood transfusions they are often subject to iron overload. In this study, we demonstrate that iron-overload mimicking condition alters bone marrow progenitor differentiation towards dendritic cells (DCs). Cells cultured in iron-enriched culture medium for seven days fail to differentiate into conventional CD11c⁺MHCII^hi DCs and fail to efficiently respond to LPS (Lipopolysaccharides). Cells appear smaller than control DCs but vital and able to perform FITC-dextran (Fluorescein isothiocyanate-dextran) endocytosis. At molecular level, cells cultured in iron-enriched conditions show increased ARG1 and PU.1, and decreased IRF8 expression. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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12 pages, 1397 KiB

Open AccessArticle

Cannabinoid Receptor 2 Modulates Maturation of Dendritic Cells and Their Capacity to Induce Hapten-Induced Contact Hypersensitivity

by Evelyn Gaffal, Andrea M. Kemter, Stefanie Scheu, Rafael Leite Dantas, Jens Vogt, Bernhard Baune, Thomas Tüting, Andreas Zimmer and Judith Alferink

Int. J. Mol. Sci. 2020, 21(2), 475; https://doi.org/10.3390/ijms21020475 - 11 Jan 2020

Cited by 8 | Viewed by 3431

Abstract

Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized Cnr2^−/− and Cnr1^−/−/Cnr2^−/− bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of Cnr1^−/− DCs. In vitro stimulated Cnr2^−/− DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in Cnr2^−/− DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities in vitro. These findings and the fact that CHS responses mediated by Cnr2^−/− DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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11 pages, 1866 KiB

Open AccessArticle

Production of IFNβ by Conventional Dendritic Cells after Stimulation with Viral Compounds and IFNβ-Independent IFNAR1-Signaling Pathways are Associated with Aggravation of Polymicrobial Sepsis

by Magdalena Howe, Jens Bauer, Anja Schulze, Sonja Kropp, Richard M. Locksley, Judith Alferink, Heike Weighardt and Stefanie Scheu

Int. J. Mol. Sci. 2019, 20(18), 4410; https://doi.org/10.3390/ijms20184410 - 7 Sep 2019

Cited by 4 | Viewed by 2973

Abstract

Viral infections are associated with increased incidence of severe sepsis. Particularly during the early stages, type I interferons (IFNs) are known mediators of detrimental effects. However, the functional role of early interferon β (IFNβ) and its cellular source during sepsis in the context of preexisting viral infections has not been defined. Using the colon ascendens stent peritonitis (CASP) model, we demonstrate that IFNβ^−/− and type I IFN receptor (IFNAR1)^−/− mice were less susceptible to sepsis after pre-stimulation with the viral mimetic poly(I:C). Wild type (WT) mice treated with poly(I:C) exhibited altered expression patterns of TNF and IL-12p40 during CASP which were dependent on IFNβ or IFNAR1, suggesting a mechanism for the increased sepsis susceptibility of WT mice. Using a double cytokine reporter mouse model, we present novel data on the simultaneous expression of IFNβ and IL-12p40 on a single cell level during polymicrobial sepsis in vivo. Conventional dendritic cells (cDCs) were identified as primary source of IFNβ and the protective cytokine IL-12p40 after CASP surgery irrespective of poly(I:C) pre-stimulation. These data demonstrated that if polymicrobial sepsis is preceded by a viral infection, IFNβ and IL-12p40 are expressed by polyfunctional cDCs suggesting that these cells can play both detrimental and beneficial roles during sepsis development. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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14 pages, 2041 KiB

Open AccessArticle

Expression and Functional Role of TRPV4 in Bone Marrow-Derived CD11c⁺ Cells

by Robbe Naert, Alejandro López-Requena, Thomas Voets, Karel Talavera and Yeranddy A. Alpizar

Int. J. Mol. Sci. 2019, 20(14), 3378; https://doi.org/10.3390/ijms20143378 - 10 Jul 2019

Cited by 11 | Viewed by 4170

Abstract

The increase in cytosolic Ca²⁺ is essential in key effector functions of dendritic cells (DCs), including differentiation, maturation, cytokine expression, and phagocytosis. Although several Ca²⁺-permeable ion channels have been described in DCs, the contribution of transient receptor potential (TRP) channels remains poorly understood. Here, we investigated whether TRPV4 plays a role in the differentiation, maturation, and phagocytosis of granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced mouse bone marrow-derived cells (BMDCs). Using intracellular Ca²⁺ imaging experiments, we found that TRPV4 was functionally expressed in the plasma membrane of immature CD11c⁺ BMDCs and that its activity and expression were downregulated in CD11c⁺ BMDCs matured with lipopolysaccharide (LPS). Comparative analysis of the GM-CSF-stimulated cells showed that Trpv4 knockout and wild-type bone marrow cultures had a similar distribution of differentiated cells, generating a heterogenous culture population rich in CD11c⁺, CD11b⁺ cells, and low levels of F4/80⁺ cells. The lack of TRPV4 did not prevent the LPS-induced nuclear translocation of NF-κB, the upregulation of the proinflammatory cytokines IL-6 and IL-12, or the upregulation of the maturation markers CD40, CD80, and CD86. In contrast, TRPV4-deficient CD11c⁺ BMDCs exhibited a significantly reduced endocytic capacity of IgG-coated beads, but the internalization of uncoated beads in the absence of TRPV4 was not affected. Taken together, our results demonstrate that TRPV4 was dispensable in the differentiation and maturation of mouse CD11c⁺ BMDCs but contributed to the mechanism underlying Fc receptor-mediated phagocytosis. Overall, our results further strengthen the role of TRPV4 in immune-related processes. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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12 pages, 1616 KiB

Open AccessCommunication

Resiquimod-Mediated Activation of Plasmacytoid Dendritic Cells Is Amplified in Multiple Sclerosis

by Marta Corsetti, Gabriella Ruocco, Serena Ruggieri, Claudio Gasperini, Luca Battistini and Elisabetta Volpe

Int. J. Mol. Sci. 2019, 20(11), 2811; https://doi.org/10.3390/ijms20112811 - 8 Jun 2019

Cited by 3 | Viewed by 3338

Abstract

Background: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. The cause of multiple sclerosis is unknown but there are several evidences that associate the genetic basis of the disease with environmental causes. An important association between viral infection and development of MS is clearly demonstrated. Viruses have a strong impact on innate immune cells. In particular, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), are able to respond to viruses and to activate the adaptive immune response. Methods: In this study we mimic viral infection using synthetic single-strand RNA, Resiquimod, and we compared the response of both DC subsets derived from healthy donors and MS patients by characterizing the expression of costimulatory molecules on the DC surface. Results: We found that pDCs from MS patients express higher levels of OX40-L, HLA-DR, and CD86 than healthy donors. Moreover, we found that blood cells from MS patients and healthy donors upon Resiquimod-stimulation are enriched in a subpopulation of pDCs, characterized by a high amount of costimulatory molecules. Conclusion: Overall, these results indicate that activation of pDCs is enhanced in MS, likely due to a latent viral infection, and that costimulatory molecules expressed on pDCs could mediate a protective response against the viral trigger of autoimmunity. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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Review

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13 pages, 863 KiB

Open AccessReview

Role of Dendritic Cell in Diabetic Nephropathy

by Hyunwoo Kim, Miyeon Kim, Hwa-Young Lee, Ho-Young Park, Hyunjhung Jhun and Soohyun Kim

Int. J. Mol. Sci. 2021, 22(14), 7554; https://doi.org/10.3390/ijms22147554 - 14 Jul 2021

Cited by 12 | Viewed by 2710

Abstract

Diabetic nephropathy (DN) is one of the most significant microvascular complications in diabetic patients. DN is the leading cause of end-stage renal disease, accounting for approximately 50% of incident cases. The current treatment options, such as optimal control of hyperglycemia and elevated blood pressure, are insufficient to prevent its progression. DN has been considered as a nonimmune, metabolic, or hemodynamic glomerular disease initiated by hyperglycemia. However, recent studies suggest that DN is an inflammatory disease, and immune cells related with innate and adaptive immunity, such as macrophage and T cells, might be involved in its development and progression. Although it has been revealed that kidney dendritic cells (DCs) accumulation in the renal tissue of human and animal models of DN require activated T cells in the kidney disease, little is known about the function of DCs in DN. In this review, we describe kidney DCs and their subsets, and the role in the pathogenesis of DN. We also suggest how to improve the kidney outcomes by modulating kidney DCs optimally in the patients with DN. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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17 pages, 1104 KiB

Open AccessReview

Oral Microbes and Mucosal Dendritic Cells, “Spark and Flame” of Local and Distant Inflammatory Diseases

by Mohamed M. Meghil and Christopher W. Cutler

Int. J. Mol. Sci. 2020, 21(5), 1643; https://doi.org/10.3390/ijms21051643 - 28 Feb 2020

Cited by 30 | Viewed by 5796

Abstract

Mucosal health and disease is mediated by a complex interplay between the microbiota (“spark”) and the inflammatory response (“flame”). Pathobionts, a specific class of microbes, exemplified by the oral microbe Porphyromonas gingivalis, live mostly “under the radar” in their human hosts, in a cooperative relationship with the indigenous microbiota. Dendritic cells (DCs), mucosal immune sentinels, often remain undisturbed by such microbes and do not alert adaptive immunity to danger. At a certain tipping point of inflammation, an “awakening” of pathobionts occurs, wherein their active growth and virulence are stimulated, leading to a dysbiosis. Pathobiont becomes pathogen, and commensal becomes accessory pathogen. The local inflammatory outcome is the Th17-mediated degenerative bone disease, periodontitis (PD). In systemic circulation of PD subjects, inflammatory DCs expand, carrying an oral microbiome and promoting Treg and Th17 responses. At distant peripheral sites, comorbid diseases including atherosclerosis, Alzheimer’s disease, macular degeneration, chronic kidney disease, and others are reportedly induced. This review will review the immunobiology of DCs, examine the complex interplay of microbes and DCs in the pathogenesis of PD and its comorbid inflammatory diseases, and discuss the role of apoptosis and autophagy in this regard. Overall, the pathophysiological mechanisms of DC-mediated chronic inflammation and tissue destruction will be summarized. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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18 pages, 946 KiB

Open AccessReview

Role of microRNAs in the Regulation of Dendritic Cell Generation and Function

by Viviana Scalavino, Marina Liso and Grazia Serino

Int. J. Mol. Sci. 2020, 21(4), 1319; https://doi.org/10.3390/ijms21041319 - 15 Feb 2020

Cited by 28 | Viewed by 5109

Abstract

Dendritic cells (DCs) are antigen-presenting cells with a key role in immune responses. They act as a link between the innate and adaptive systems and they can induce and maintain immunologic tolerance. DCs are subdivided into conventional and plasmacytoid DCs. These cell subsets originate from the same bone marrow precursors and their differentiation process is determined by several extrinsic and intrinsic factors, such as cytokines, transcription factors, and miRNAs. miRNAs are small non-coding RNAs that play a crucial role in modulating physiological and pathological processes mediated by DCs. miRNA deregulation affects many inflammatory conditions and diseases. The aim of this review was to underline the importance of miRNAs in inflammatory processes mediated by DCs in physiological and pathological conditions and to highlight their potential application for future therapies. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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24 pages, 1407 KiB

Open AccessReview

Distinct Subcellular Compartments of Dendritic Cells Used for Cross-Presentation

by Jun Imai, Mayu Otani and Takahiro Sakai

Int. J. Mol. Sci. 2019, 20(22), 5606; https://doi.org/10.3390/ijms20225606 - 9 Nov 2019

Cited by 6 | Viewed by 4121

Abstract

Dendritic cells (DCs) present exogenous protein-derived peptides on major histocompatibility complex class I molecules to prime naïve CD8⁺ T cells. This DC specific ability, called cross-presentation (CP), is important for the activation of cell-mediated immunity and the induction of self-tolerance. Recent research revealed that endoplasmic reticulum-associated degradation (ERAD), which was first identified as a part of the unfolded protein response—a quality control system in the ER—plays a pivotal role in the processing of exogenous proteins in CP. Moreover, DCs express a variety of immuno-modulatory molecules and cytokines to regulate T cell activation in response to the environment. Although both CP and immuno-modulation are indispensable, contrasting ER conditions are required for their correct activity. Since ERAD substrates are unfolded proteins, their accumulation may result in ER stress, impaired cell homeostasis, and eventually apoptosis. In contrast, activation of the unfolded protein response should be inhibited for DCs to express immuno-modulatory molecules and cytokines. Here, we review recent advances on antigen CP, focusing on intracellular transport routes for exogenous antigens and distinctive subcellular compartments involved in ERAD. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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48 pages, 1934 KiB

Open AccessReview

Immunobiology of Atherosclerosis: A Complex Net of Interactions

by Beatriz Herrero-Fernandez, Raquel Gomez-Bris, Beatriz Somovilla-Crespo and Jose Maria Gonzalez-Granado

Int. J. Mol. Sci. 2019, 20(21), 5293; https://doi.org/10.3390/ijms20215293 - 24 Oct 2019

Cited by 88 | Viewed by 9916

Abstract

Cardiovascular disease is the leading cause of mortality worldwide, and atherosclerosis the principal factor underlying cardiovascular events. Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction, intimal lipid deposition, smooth muscle cell proliferation, cell apoptosis and necrosis, and local and systemic inflammation, involving key contributions to from innate and adaptive immunity. The balance between proatherogenic inflammatory and atheroprotective anti-inflammatory responses is modulated by a complex network of interactions among vascular components and immune cells, including monocytes, macrophages, dendritic cells, and T, B, and foam cells; these interactions modulate the further progression and stability of the atherosclerotic lesion. In this review, we take a global perspective on existing knowledge about the pathogenesis of immune responses in the atherosclerotic microenvironment and the interplay between the major innate and adaptive immune factors in atherosclerosis. Studies such as this are the basis for the development of new therapies against atherosclerosis. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)

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