Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation

Abstract Dendritic cells (DCs) are key regulators of innate and acquired immunity. The maturation of DCs is directed by signal transduction events downstream of toll-like receptors (TLRs) and other pattern recognition receptors. Here, we demonstrate that, in mouse DCs, TLR agonists stimulate a profound metabolic transition to aerobic glycolysis, similar to the Warburg metabolism displayed by cancer cells. This metabolic switch depends on the phosphatidyl inositol 3′-kinase/Akt pathway, is antagonized by the adenosine monophosphate (AMP)–activated protein kinase (AMPK), and is required for DC maturation. The metabolic switch induced by DC activation is antagonized by the antiinflammatory cytokine interleukin-10. Our data pinpoint TLR-mediated metabolic conversion as essential for DC maturation and function and reveal it as a potential target for intervention in the control of excessive inflammation and inappropriately regulated immune responses.

Download Full-text

Effects ofStreptococcus mutanson Dendritic Cell Activation and Function

Journal of Dental Research ◽

10.1177/0022034511412970 ◽

2011 ◽

Vol 90 (10) ◽

pp. 1221-1227 ◽

Cited By ~ 4

Author(s):

J.P. Butcher ◽

J. Malcolm ◽

R.A. Benson ◽

D.M. Deng ◽

J.M. Brewer ◽

...

Keyword(s):

Dendritic Cell ◽

Cell Activation ◽

Dendritic Cell Activation ◽

And Function

Download Full-text

In vitroinhibitory effects of thymol and carvacrol on dendritic cell activation and function

Pharmaceutical Biology ◽

10.3109/13880209.2015.1055579 ◽

2015 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Zahra Amirghofran ◽

Hossein Ahmadi ◽

Mohammad Hossein Karimi ◽

Fathollah Kalantar ◽

Nasser Gholijani ◽

...

Keyword(s):

Dendritic Cell ◽

Cell Activation ◽

Dendritic Cell Activation ◽

And Function

Download Full-text

Replicating Adenovirus-SIV Immunization of Rhesus Macaques Induces Mucosal Dendritic Cell Activation and Function Leading to Rectal Immune Responses

Frontiers in Immunology ◽

10.3389/fimmu.2019.00779 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 6

Author(s):

Eun-Ju Ko ◽

Sabrina Helmold Hait ◽

Gospel Enyindah-Asonye ◽

Mohammad Arif Rahman ◽

Tanya Hoang ◽

...

Keyword(s):

Dendritic Cell ◽

Immune Responses ◽

Cell Activation ◽

Rhesus Macaques ◽

Dendritic Cell Activation ◽

And Function

Download Full-text

Suppression of Dendritic Cell Activation by Anthrax Lethal Toxin and Edema Toxin Depends on Multiple Factors Including Cell Source, Stimulus Used, and Function Tested

DNA and Cell Biology ◽

10.1089/dna.2008.0760 ◽

2008 ◽

Vol 27 (12) ◽

pp. 637-648 ◽

Cited By ~ 15

Author(s):

Ping-Jen (Joe) Chou ◽

Catherine A. Newton ◽

Izabella Perkins ◽

Herman Friedman ◽

Thomas W. Klein

Keyword(s):

Dendritic Cell ◽

Cell Activation ◽

Lethal Toxin ◽

Anthrax Lethal Toxin ◽

Dendritic Cell Activation ◽

Multiple Factors ◽

Edema Toxin ◽

Cell Source ◽

And Function

Download Full-text

Dendritic Cell Activation and Cytokine Production Induced by Group B Neisseria meningitidis: Interleukin-12 Production Depends on Lipopolysaccharide Expression in Intact Bacteria

Infection and Immunity ◽

10.1128/iai.69.7.4351-4357.2001 ◽

2001 ◽

Vol 69 (7) ◽

pp. 4351-4357 ◽

Cited By ~ 58

Author(s):

Garth L. J. Dixon ◽

Phillippa J. Newton ◽

Benjamin M. Chain ◽

David Katz ◽

Svein Rune Andersen ◽

...

Keyword(s):

Neisseria Meningitidis ◽

Parent Strain ◽

Cell Activation ◽

Cytokine Production ◽

Costimulatory Molecules ◽

Interleukin 12 ◽

Dendritic Cell Activation ◽

Tnf Α ◽

High Level ◽

Dc Maturation

ABSTRACT Interactions between dendritic cells (DCs) and microbial pathogens are fundamental to the generation of innate and adaptive immune responses. Upon stimulation with bacteria or bacterial components such as lipopolysaccharide (LPS), immature DCs undergo a maturation process that involves expression of costimulatory molecules, HLA molecules, and cytokines and chemokines, thus providing critical signals for lymphocyte development and differentiation. In this study, we investigated the response of in vitro-generated human DCs to a serogroup B strain of Neisseria meningitidis compared to an isogenic mutant lpxA strain totally deficient in LPS and purified LPS from the same strain. We show that the parent strain,lpxA mutant, and meningococcal LPS all induce DC maturation as measured by increased surface expression of costimulatory molecules and HLA class I and II molecules. Both the parent and lpxAstrains induced production of tumor necrosis factor alpha (TNF-α), interleukin-1α (IL-1α), and IL-6 in DCs, although the parent was the more potent stimulus. In contrast, high-level IL-12 production was only seen with the parent strain. Compared to intact bacteria, purified LPS was a very poor inducer of IL-1α, IL-6, and TNF-α production and induced no detectable IL-12. Addition of exogenous LPS to thelpxA strain only partially restored cytokine production and did not restore IL-12 production. These data show that non-LPS components of N. meningitidis induce DC maturation, but that LPS in the context of the intact bacterium is required for high-level cytokine production, especially that of IL-12. These findings may be useful in assessing components of N. meningitidis as potential vaccine candidates.

Download Full-text

Simultaneous Blocking of Human Toll-Like Receptors 2 and 4 Suppresses Myeloid Dendritic Cell Activation Induced by Mycobacterium bovis Bacillus Calmette-Guérin Peptidoglycan

Infection and Immunity ◽

10.1128/iai.71.8.4238-4249.2003 ◽

2003 ◽

Vol 71 (8) ◽

pp. 4238-4249 ◽

Cited By ~ 119

Author(s):

Junji Uehori ◽

Misako Matsumoto ◽

Shoutaro Tsuji ◽

Takashi Akazawa ◽

Osamu Takeuchi ◽

...

Keyword(s):

Dendritic Cell ◽

Mycobacterium Bovis ◽

Cell Activation ◽

Hek293 Cells ◽

Myeloid Dendritic Cell ◽

Dendritic Cell Activation ◽

Double Knockout ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Dc Maturation

ABSTRACT The Mycobacterium bovis bacillus Calmette-Guérin (BCG) cell wall skeleton (CWS) consists of mycolic acids, arabinogalactan, and peptidoglycan (PGN) and activates Toll-like receptor 2 (TLR2) and TLR4. Here we investigated the ability of the essential portion of highly purified BCG CWS to support the TLR agonist function by using the following criteria: myeloid dendritic cell (DC) maturation, i.e., tumor necrosis factor alpha (TNF-α) production and CD83/CD86 up-regulation. The purified PGN region was sufficient to activate TLR2 and TLR4 in mouse DCs and macrophages; in TLR2 and TLR4 double-knockout cells the BCG PGN-mediated TNF-α production ability was completely impaired. Likewise, stimulation with BCG CWS of HEK293 cells expressing either human TLR2 or TLR4, MD-2, and CD14 resulted in NF-κB activation as determined by a reporter assay. Notably, specific blockers of extracellular human TLR2 (an original cocktail of monoclonal antibodies TLR2.45 and TH2.1) and TLR4 (E5531) inhibited BCG CWS-mediated NF-κB activation by 80%. Using this human TLR blocking system, we tested whether human myeloid DC maturation was TLR2 and TLR4 dependent. BCG PGN-mediated DC maturation was blocked by 70% by suppression of both TLR2 and TLR4 and by 30 to 40% by suppression of either of these TLRs. Similar but less profound suppression of BCG CWS-mediated DC maturation was observed. Hence, the presence of BCG PGN is a minimal requirement for activation of both TLR2 and TLR4 in human DCs, unlike the presence of PGNs of gram-positive bacteria, which activate only TLR2. Unexpectedly, however, BCG PGN, unlike BCG CWS, barely activated NF-κB in HEK293 cells coexpressing TLR2 plus TLR1, TLR2 plus TLR4, TLR2 plus TLR6, or TLR2 plus TLR10, suggesting that PGN receptors other than TLR2 and TLR4 present on human DCs but not on HEK293 cells are involved in TLR signaling for DC activation.

Download Full-text