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Disarmed by density: A glycolytic break for immunostimulatory dendritic cells?

Nasi A, Rethi B - Oncoimmunology (2013)

Bottom Line: We observed a cell concentration-dependent differentiation switch among cultured dendritic cells (DCs) triggered by lactic acid, a product of glycolytic metabolism.In particular, while interleukin (IL)-12, IL-23, and tumor necrosis factor α (TNFα)-producing, migratory DCs developed in sparse cultures, IL-10-producing, non-migratory DCs differentiated in dense cultures.This points to a novel opportunity for tailoring DC-based anticancer therapies through metabolism modulation in developing DCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology; Tumor and Cell Biology; Karolinska Institutet; Stockholm, Sweden.

ABSTRACT
We observed a cell concentration-dependent differentiation switch among cultured dendritic cells (DCs) triggered by lactic acid, a product of glycolytic metabolism. In particular, while interleukin (IL)-12, IL-23, and tumor necrosis factor α (TNFα)-producing, migratory DCs developed in sparse cultures, IL-10-producing, non-migratory DCs differentiated in dense cultures. This points to a novel opportunity for tailoring DC-based anticancer therapies through metabolism modulation in developing DCs.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Rewiring dendritic cell differentiation upon the accumulation of lactic acid. Monocyte-derived dendritic cells (DCs) developing in sparse monocytic cultures show a superior ability to produce pro-inflammatory cytokines, to elicit TH1 responses and to migrate toward the lymphoid tissue-derived chemotactic agent chemokine (C-C motif) ligand 19 (CCL19). On the contrary, DCs differentiating in dense cultures produce interleukin (IL)-10 but no pro-inflammatory cytokines upon activation. In addition, DCs originating in dense cultures maintain a relatively high plasticity and can trans-differentiate to osteoclasts. A key role for lactic acid in rewiring DC functions was demonstrated by interfering with lactic acid production in dense cultures, which increased IL-12 and decreased IL-10 production, and by adding lactic acid to sparse cultures, which resulted in opposite effects. CCR7, chemokine (C-C motif) receptor 7; TNFα, tumor necrosis factor α.
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Figure 1: Figure 1. Rewiring dendritic cell differentiation upon the accumulation of lactic acid. Monocyte-derived dendritic cells (DCs) developing in sparse monocytic cultures show a superior ability to produce pro-inflammatory cytokines, to elicit TH1 responses and to migrate toward the lymphoid tissue-derived chemotactic agent chemokine (C-C motif) ligand 19 (CCL19). On the contrary, DCs differentiating in dense cultures produce interleukin (IL)-10 but no pro-inflammatory cytokines upon activation. In addition, DCs originating in dense cultures maintain a relatively high plasticity and can trans-differentiate to osteoclasts. A key role for lactic acid in rewiring DC functions was demonstrated by interfering with lactic acid production in dense cultures, which increased IL-12 and decreased IL-10 production, and by adding lactic acid to sparse cultures, which resulted in opposite effects. CCR7, chemokine (C-C motif) receptor 7; TNFα, tumor necrosis factor α.

Mentions: We have recently identified a potent autocrine pathway that operate on developing DCs and provide a surprising contribution to the phenotypic and functional heterogeneity of monocyte-derived DCs.5 We demonstrated that lactic acid, an abundant product of aerobic glycolysis, accumulates in dense DC cultures and induces a powerful anti-inflammatory differentiation program. Indeed, high cell culture densities (2 x 106 monocytes/mL) resulted in the development of a mixture of CD1a+CD14−CD209+ and CD1a−CD14+CD209+ DCs that produced high levels of interleukin (IL)-10 but no pro-inflammatory cytokines upon Toll-like receptor (TLR) stimulation. In addition, the DCs developing in dense cultures exhibited defective migratory responses to the lymphoid tissue-derived chemotactic agent chemokine (C-C motif) ligand 19 (CCL19) and remained uncommitted to DC functions, as demonstrated by their trans-differentiation to osteoclasts. By decreasing culture density to 0.5–1 x 106 monocytes/mL, we mainly obtained CD1a+CD14− DCs, which produced modest levels of both IL-10 and pro-inflammatory cytokines upon activation. Conversely, the further dilution of cell cultures (0.125–0.25 x 106 monocytes/mL) primed DCs to produce very high levels of IL-12, IL-23 and tumor necrosis factor α (TNFα) upon activation (but no IL-10), and these cells were easily mobilized by CCL19 (Fig. 1). These DCs obtained their functional polarization already in the first 1–2 d of culture, and changing the culture density later did not influence their cytokine secretion profile.


Disarmed by density: A glycolytic break for immunostimulatory dendritic cells?

Nasi A, Rethi B - Oncoimmunology (2013)

Figure 1. Rewiring dendritic cell differentiation upon the accumulation of lactic acid. Monocyte-derived dendritic cells (DCs) developing in sparse monocytic cultures show a superior ability to produce pro-inflammatory cytokines, to elicit TH1 responses and to migrate toward the lymphoid tissue-derived chemotactic agent chemokine (C-C motif) ligand 19 (CCL19). On the contrary, DCs differentiating in dense cultures produce interleukin (IL)-10 but no pro-inflammatory cytokines upon activation. In addition, DCs originating in dense cultures maintain a relatively high plasticity and can trans-differentiate to osteoclasts. A key role for lactic acid in rewiring DC functions was demonstrated by interfering with lactic acid production in dense cultures, which increased IL-12 and decreased IL-10 production, and by adding lactic acid to sparse cultures, which resulted in opposite effects. CCR7, chemokine (C-C motif) receptor 7; TNFα, tumor necrosis factor α.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926870&req=5

Figure 1: Figure 1. Rewiring dendritic cell differentiation upon the accumulation of lactic acid. Monocyte-derived dendritic cells (DCs) developing in sparse monocytic cultures show a superior ability to produce pro-inflammatory cytokines, to elicit TH1 responses and to migrate toward the lymphoid tissue-derived chemotactic agent chemokine (C-C motif) ligand 19 (CCL19). On the contrary, DCs differentiating in dense cultures produce interleukin (IL)-10 but no pro-inflammatory cytokines upon activation. In addition, DCs originating in dense cultures maintain a relatively high plasticity and can trans-differentiate to osteoclasts. A key role for lactic acid in rewiring DC functions was demonstrated by interfering with lactic acid production in dense cultures, which increased IL-12 and decreased IL-10 production, and by adding lactic acid to sparse cultures, which resulted in opposite effects. CCR7, chemokine (C-C motif) receptor 7; TNFα, tumor necrosis factor α.
Mentions: We have recently identified a potent autocrine pathway that operate on developing DCs and provide a surprising contribution to the phenotypic and functional heterogeneity of monocyte-derived DCs.5 We demonstrated that lactic acid, an abundant product of aerobic glycolysis, accumulates in dense DC cultures and induces a powerful anti-inflammatory differentiation program. Indeed, high cell culture densities (2 x 106 monocytes/mL) resulted in the development of a mixture of CD1a+CD14−CD209+ and CD1a−CD14+CD209+ DCs that produced high levels of interleukin (IL)-10 but no pro-inflammatory cytokines upon Toll-like receptor (TLR) stimulation. In addition, the DCs developing in dense cultures exhibited defective migratory responses to the lymphoid tissue-derived chemotactic agent chemokine (C-C motif) ligand 19 (CCL19) and remained uncommitted to DC functions, as demonstrated by their trans-differentiation to osteoclasts. By decreasing culture density to 0.5–1 x 106 monocytes/mL, we mainly obtained CD1a+CD14− DCs, which produced modest levels of both IL-10 and pro-inflammatory cytokines upon activation. Conversely, the further dilution of cell cultures (0.125–0.25 x 106 monocytes/mL) primed DCs to produce very high levels of IL-12, IL-23 and tumor necrosis factor α (TNFα) upon activation (but no IL-10), and these cells were easily mobilized by CCL19 (Fig. 1). These DCs obtained their functional polarization already in the first 1–2 d of culture, and changing the culture density later did not influence their cytokine secretion profile.

Bottom Line: We observed a cell concentration-dependent differentiation switch among cultured dendritic cells (DCs) triggered by lactic acid, a product of glycolytic metabolism.In particular, while interleukin (IL)-12, IL-23, and tumor necrosis factor α (TNFα)-producing, migratory DCs developed in sparse cultures, IL-10-producing, non-migratory DCs differentiated in dense cultures.This points to a novel opportunity for tailoring DC-based anticancer therapies through metabolism modulation in developing DCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology; Tumor and Cell Biology; Karolinska Institutet; Stockholm, Sweden.

ABSTRACT
We observed a cell concentration-dependent differentiation switch among cultured dendritic cells (DCs) triggered by lactic acid, a product of glycolytic metabolism. In particular, while interleukin (IL)-12, IL-23, and tumor necrosis factor α (TNFα)-producing, migratory DCs developed in sparse cultures, IL-10-producing, non-migratory DCs differentiated in dense cultures. This points to a novel opportunity for tailoring DC-based anticancer therapies through metabolism modulation in developing DCs.

No MeSH data available.


Related in: MedlinePlus