Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-β). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases, as well as in tumor immune escape mechanisms. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. The kinetics of glycolysis after TLR7/9 triggering may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR. This could explain a delayed glycolysis in mouse PDC. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statin or LXR agonist treatment) in these cells. Finally, lipid-activated nuclear receptors (i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-κB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role.

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Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

F1000Research ◽

10.12688/f1000research.11332.1 ◽

2017 ◽

Vol 6 ◽

pp. 456 ◽

Cited By ~ 9

Author(s):

Philippe Saas ◽

Alexis Varin ◽

Sylvain Perruche ◽

Adam Ceroi

Keyword(s):

Dendritic Cells ◽

Lipid Metabolism ◽

Nuclear Receptors ◽

Immune Cells ◽

Transforming Growth Factor ◽

Plasmacytoid Dendritic Cell ◽

Innate Immune ◽

Type I ◽

Innate Immune Cells ◽

Immune Functions

There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-β). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. Some differences may be related to the origin of PDC (human versus mouse PDC or blood-sorted versus FLT3 ligand stimulated-bone marrow-sorted PDC). The kinetics of glycolysis may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR, explaining a delayed glycolysis. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statins or LXR agonists) in these cells. Finally, lipid-activated nuclear receptors (i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-κB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role.

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Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING

The FASEB Journal ◽

10.1096/fj.201601093r ◽

2017 ◽

Vol 31 (7) ◽

pp. 3107-3115 ◽

Cited By ~ 6

Author(s):

Christine Rueckert ◽

Ulfert Rand ◽

Urmi Roy ◽

Bahram Kasmapour ◽

Till Strowig ◽

...

Keyword(s):

Immune Cells ◽

Innate Immune ◽

Type I ◽

Innate Immune Cells ◽

Type I Ifn ◽

Cyclic Dinucleotides

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Natural Killer Dendritic Cells Enhance Immune Responses Elicited byα-Galactosylceramide-Stimulated Natural Killer T Cells

BioMed Research International ◽

10.1155/2013/460706 ◽

2013 ◽

Vol 2013 ◽

pp. 1-18 ◽

Cited By ~ 3

Author(s):

Sung Won Lee ◽

Hyun Jung Park ◽

Nayoung Kim ◽

Seokmann Hong

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Natural Killer ◽

Immune Cells ◽

Tumor Antigens ◽

Nkt Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Natural Killer T

Natural killer dendritic cells (NKDCs) possess potent anti-tumor activity, but the cellular effect of NKDC interactions with other innate immune cells is unclear. In this study, we demonstrate that the interaction of NKDCs and natural killer T (NKT) cells is required for the anti-tumor immune responses that are elicited byα-galactosylceramide (α-GC) in mice. The rapid and strong expression of interferon-γby NKDCs afterα-GC stimulation was dependent on NKT cells. Various NK and DC molecular markers and cytotoxic molecules were up-regulated followingα-GC administration. This up-regulation could improve NKDC presentation of tumor antigens and increase cytotoxicity against tumor cells. NKDCs were required for the stimulation of DCs, NK cells, and NKT cells. The strong anti-tumor immune responses elicited byα-GC may be due to the down-regulation of regulatory T cells. Furthermore, the depletion of NKDCs dampened the tumor clearance mediated byα-GC-stimulated NKT cellsin vivo. Taken together, these results indicate that complex interactions of innate immune cells might be required to achieve optimal anti-tumor immune responses during the early stages of tumorigenesis.

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Calreticulin Promotes Immunity Against Acute Myeloid Leukemia Cells in Vivo

Blood ◽

10.1182/blood.v124.21.996.996 ◽

2014 ◽

Vol 124 (21) ◽

pp. 996-996

Author(s):

Xiufen Chen ◽

Dominick Fosco ◽

Douglas E. Kline ◽

Justin Kline

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cell Surface ◽

Vector Control ◽

Immune Cells ◽

Myeloid Leukemia ◽

Innate Immune ◽

Innate Immune Cells

Abstract Pre-apoptotic cancer cells release internalized calreticulin (CRT) to their surface prior to death, which acts as an ‘eat-me’ signal to local phagocytes. Chemotherapy and irradiation, which can induce immunogenic cell death through CRT translocation, can also result in local and/or systemic immune suppression in the host. To bypass the requirement of exposing the host to chemotherapy to induce translocation of CRT to the cell surface, murine acute myeloid leukemia (AML) cells (C1498), were engineered to constitutively express cell surface CRT (C1498.CRT). Vector control C1498 or C1498.CRT cells were inoculated intravenously (IV) into C57BL/6 mice. Significantly prolonged survival was observed in hosts harboring C1498.CRT versus vector control C1498 cells systemically. The survival benefit were abrogated in both Rag2-/- hosts or by depletion of T cells with anti-CD4 plus anti-CD8 antibodies, arguing that the immune-mediated effect of cell-surface CRT expression is dependent upon a functional adaptive immune system. More strikingly, systemic inoculation with C1498.CRT cells expressing the model SIYRYYGL (SIY) peptide antigen (C1498.SIY.CRT cells) resulted in almost complete protection from AML development (>90% long term survival vs. 10% of C1498.SIY vector control cells). All animals surviving a primary C1498.SIY.CRT challenge rejected a subsequent re-challenge with C1498.SIY cells, suggesting that CRT-expressing AML cells promote immunologic memory. Significantly enhanced expansion and unregulated IFNγ production were observed among SIY-specific T cell receptor transgenic CD8+ 2C T cells following their adoptive transfer into hosts bearing C1498.SIY.CRT AML cells versus vector control C1498.SIY cells. Interestingly, CRT expression on AML cells did not promote their in vivo phagocytosis by innate immune cells, specifically splenic CD8a+ dendritic cells known to engulf AML cells following their IV inoculation. IL-12 production by CD8α+CD11c+ dendritic cells which had engulfed C1498 and C1498.CRT cells in vivo was similarly induced, and cross-presentation of the SIY antigen to 2C T cells ex vivo by purified CD8a+DCs following in vivo exposure to C1498.SIY or C1498.SIY.CRT cells was also similar. In conclusion, it is clear that expression on CRT on the surface of AML cells leads to robust leukemia-specific T cell activation and expansion resulting in prolonged leukemia-specific survival in AML-bearing animals. Although a direct effect of CRT on innate immune cells, such as dendritic cells, is suspected, the molecular mechanism underlying the “CRT effect” remains unclear, and is being explored further through gene expression analysis in purified DCs which have engulfed CRT-expressing or control AML cells in vivo, as well as in animals genetically deficient in the putative CRT receptor, LRP, in dendritic cells. It will be of interest to analyze spontaneous CRT expression on AML cells from human samples and to correlate cell surface CRT expression with the presence or absence of spontaneous T cell responses to known AML antigens and with clinical outcomes. Disclosures No relevant conflicts of interest to declare.

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Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma

10.1101/248807 ◽

2018 ◽

Author(s):

Carlos R. Figueiredo ◽

Ricardo A. Azevedo ◽

Sasha Mousdell ◽

Pedro T. Resende-Lara ◽

Lucy Ireland ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Metastatic Melanoma ◽

Immune Cells ◽

Tumour Microenvironment ◽

Innate Immune ◽

Innate Immune Cells ◽

Adaptive Immune Cells ◽

Cancer Immunotherapies

ABSTRACTMounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells’ immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

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Macrophages and Dendritic Cells Are Not the Major Source of Pro-Inflammatory Cytokines Upon SARS-CoV-2 Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.647824 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marc A. Niles ◽

Patricia Gogesch ◽

Stefanie Kronhart ◽

Samira Ortega Iannazzo ◽

Georg Kochs ◽

...

Keyword(s):

Dendritic Cells ◽

Inflammatory Cytokines ◽

Immune Cells ◽

Influenza A ◽

Innate Immune ◽

Innate Immune Cells ◽

M2 Macrophages ◽

Myeloid Dendritic Cells ◽

M1 And M2 Macrophages ◽

Pro Inflammatory Cytokines

The exact role of innate immune cells upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their contribution to the formation of the corona virus-induced disease (COVID)-19 associated cytokine storm is not yet fully understood. We show that human in vitro differentiated myeloid dendritic cells (mDC) as well as M1 and M2 macrophages are susceptible to infection with SARS-CoV-2 but are not productively infected. Furthermore, infected mDC, M1-, and M2 macrophages show only slight changes in their activation status. Surprisingly, none of the infected innate immune cells produced the pro-inflammatory cytokines interleukin (IL)−6, tumor necrosis factor (TNF)-α, or interferon (IFN)−α. Moreover, even in co-infection experiments using different stimuli, as well as non-influenza (non-flu) or influenza A (flu) viruses, only very minor IL-6 production was induced. In summary, we conclude that mDC and macrophages are unlikely the source of the first wave of cytokines upon infection with SARS-CoV-2.

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Regulation of Hierarchical Clustering and Activation of Innate Immune Cells by Dendritic Cells

Immunity ◽

10.1016/j.immuni.2008.09.017 ◽

2008 ◽

Vol 29 (5) ◽

pp. 819-833 ◽

Cited By ~ 121

Author(s):

Suk-Jo Kang ◽

Hong-Erh Liang ◽

Boris Reizis ◽

Richard M. Locksley

Keyword(s):

Dendritic Cells ◽

Hierarchical Clustering ◽

Immune Cells ◽

Innate Immune ◽

Innate Immune Cells

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The Role of TLR-4 and Galectin-3 Interaction in Acute Pancreatitis

Serbian Journal of Experimental and Clinical Research ◽

10.2478/sjecr-2019-0067 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Milica Dimitrijevic Stojanovic ◽

Bojan Stojanovic ◽

Nebojsa Arsenijevic ◽

Bojana Stojanovic

Keyword(s):

Acute Pancreatitis ◽

Immune Cells ◽

Pancreatic Tissue ◽

Experimental Models ◽

Innate Immune ◽

Type I ◽

Innate Immune Cells ◽

Enhanced Production ◽

Galectin 3

AbstractToll-like receptor-4 (TLR-4) is a member of evolutionarily conserved type I transmembrane proteins that can initiate sterile inflammatory cascade in the pancreas. Expression of TLR-4 is up-regulated in pancreatic tissue, as well as, on peripheral blood innate immune cells in human and experimental models of acute pancreatitis. TLR-4 plays important pro-inflammatory roles during development of acute pancreatitis: it recognize alarmins released from injured acinar cells and promotes activation and infiltration of innate immune cells after the premature and intraacinar activation of tripsinogen. Galectin-3 is β-galactoside-binding lectin that plays pro-inflammatory roles in a variety autoimmune diseases, acute bacterial infections and during tumorigenesis. It is reported that Galectin-3 is alarmin in experimental models of neuroinflammation and binds to TLR-4 promoting the pro-inflammatory phenotype of microglia. Also, in experimental model of acute pancreatitis Galectin-3 is colocalized with TLR-4 on innate inflammatory cells resulted in enhanced production of inflammatory cytokines, TNF-α and IL-1β, increased infiltration of pro-inflammatory N1 neutrophils, macrophages and dendritic cells and increased damage of pancreatic tissue. This review paper discusses the role of TLR-4/Gal-3 axis in the pathogenesis of acute pancreatitis.

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Tubular lysosome biogenesis in innate immune cells

10.32920/ryerson.14663805.v1 ◽

2021 ◽

Author(s):

Amra Saric

Keyword(s):

Dendritic Cells ◽

Antigen Presentation ◽

Immune Cells ◽

Cell Function ◽

Fluid Phase ◽

Adaptor Proteins ◽

Innate Immune ◽

Innate Immune Cells ◽

Lysosome Biogenesis ◽

Dynamic Structures

Lysosomes are essential organelles required for breakdown of endocytic and biosynthetic cargo, pathogen killing and autophagy. In most cells, lysosomes are typically small punctate structures. By contrast, innate immune cells like macrophages and dendeitic cells that have been exposed to bacterial lipopolysaccharids (LPS) exhibit strikingly tubular lysosomes (TLs) and lysosome-related major histocompatility class II (MHCII) compartments (MIIC), respectively. TLs are suggested to play a role in phagosome maturation and retention of fluid-phase endocytic uptake in activated macrophages. In addition, the dendritic cell tubular MIIC (tMIIC) may be involved in antigen presentation. Since remarkably little was known about how tubular lysosomes form, I took to investigate the molecular requirements for this process in macrophages and dendritic cells and present my findings in this thesis. Here I confirm that microtubules are necessary as a template for lysosome tabulation, along with dynein and kinesin microtubule-dependendent motors. We were first to identify molecular components necessary for lysosome tabulation; TL biogenesis required the concerted action of the Ar18b GTPasem along with its effector SKIP, a kinesin adaptor proteins for dynein and kinesin, respectively. Importantly, we observed that TLs are highly dynamic structures whereas punctate lysosomes are conspicuously more static. I also present evidence that mTOR, a lysosomal protein kinase, is required for LPS-induced TL biogenesis and cell surface delivery of MHCII in macrophages and dendritic cells. First, I show that the MyD88-P13K-Akt-mTOR signaling pathway regulates LPS-induced lysosome tabulation. Second, I demonstrate that mTOR is required for anterograde lysosomal transport suggesting that this kinase may regulate tabulation and antigen presentation by modulating the microtubule-based motor activity of lysosomes. Finally I present preliminary data on the properties of tubular lysosomes compare to punctate lysosomes in an effort to characterize these organelles. Among the data presented is evidence that total lysosomal volume increases significantly upon tabulation, which may have important underlying implications in antigen sampling and processing. Overall, my work has expanded on our knowledge on our knowledge of how morphology and trafficking of lysosomes is modulated in immune cells, which may alter cell function.

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