. 2019 Dec 3;30(6):1055-1074.e8.

doi: 10.1016/j.cmet.2019.10.004. Epub 2019 Nov 7.

Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4⁺ T Cell Metabolic Rewiring

Valentina Pucino¹, Michelangelo Certo¹, Vinay Bulusu², Danilo Cucchi³, Katriona Goldmann³, Elena Pontarini³, Robert Haas³, Joanne Smith³, Sarah E Headland³, Kevin Blighe³, Massimiliano Ruscica⁴, Frances Humby³, Myles J Lewis³, Jurre J Kamphorst², Michele Bombardieri³, Costantino Pitzalis³, Claudio Mauro⁵

Affiliations

¹ Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
² Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
³ William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁴ Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
⁵ Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. Electronic address: c.mauro@bham.ac.uk.

PMID: 31708446
PMCID: PMC6899510
DOI: 10.1016/j.cmet.2019.10.004

Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4⁺ T Cell Metabolic Rewiring

Valentina Pucino et al. Cell Metab. 2019.

. 2019 Dec 3;30(6):1055-1074.e8.

doi: 10.1016/j.cmet.2019.10.004. Epub 2019 Nov 7.

Authors

Affiliations

¹ Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
² Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
³ William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁴ Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
⁵ Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. Electronic address: c.mauro@bham.ac.uk.

PMID: 31708446
PMCID: PMC6899510
DOI: 10.1016/j.cmet.2019.10.004

Abstract

Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4⁺ T cells. SLC5A12-mediated lactate uptake into CD4⁺ T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4⁺ T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.

Keywords: T cell; cytokines; immunometabolism; inflammation; lactate; lactate transporter; metabolic crosstalk; signaling; translational research.

PubMed Disclaimer

Conflict of interest statement

J.J.K. is an employee of and shareholder in Rheos Medicines, Inc.

Figures

**Figure 1**
SLC5A12 Expression by CD4⁺ T Cells Is Regulated by Activating and Inflammatory Stimuli (A–C) Representative flow cytometry plots of SLC5A12 expression by CD4⁺ or CD8⁺ T cells from non-activated (n = 3; A) or anti-CD3 mAb-activated (n = 6; B) HC PBMCs. Quantification shown in (C). (D–F) Representative flow cytometry histograms (D and E) and quantification (F) of SLC5A12 expression by CD4⁺ T cells from non-activated HC (n = 4) and RA (n = 4; D and F), or anti-CD3 mAb-activated HC (n = 4) and RA (n = 5; E and F) PBMCs. CD4⁺ T cells from non-activated RA SFMCs (n = 8; E and F) were also analyzed. Briefly, PBMCs were cultured in RPMI medium supplemented with 5% RA or HC autologous blood serum (BS), or 5% RA synovial fluid (SF); SFMCs were cultured in RPMI medium supplemented with 5% autologous SF. (G) Representative flow cytometry histograms (left) and quantification (right) of SLC5A12 expression by CD4⁺ T cells from non-activated or anti-CD3 mAb-activated RA SFMCs. Briefly, cells were cultured in RPMI medium supplemented with 5% FBS (n = 3), 5% autologous BS (n = 8) or 5% autologous RA SF (n = 8). Activated RA PBMCs cultured in 5% BS RPMI (n = 5) were used as controls (H). MFI, mean fluorescent intensity. (H) Representative flow cytometry histograms (left) and quantification (right) of SLC5A12 expression by CD4⁺ T cells from RA SFMCs (n = 5) incubated with 3C7 mAb or control rat sera. (I and J) SLC5A12 mRNA (n = 5; I) and protein (representative western blots [left] and densitometric quantification [right; n = 3]; J) expression by CD4⁺ T cells isolated from HC PBMCs, then activated with anti-CD3 and anti-CD28 mAb in the presence of sodium lactate (10 mM) and/or SLC5A12 Ab, or left untreated. Lactate-untreated CD4⁺ T cells (CN, dotted line) set to 1. One-way ANOVA (C and F) or two-tailed Student’s t test (G–J). Data expressed as mean ± SEM. ^∗p ≤ 0.05; ^∗∗p ≤ 0.01; ^∗∗∗p ≤ 0.001. See also Figures S1, S2, and S3.

**Figure 2**
Lactate Uptake by CD4⁺ T Cells Impacts Intracellular Utilization of Central Carbon Metabolic Pathways (A) Glucose and glutamine uptake rates for CD4⁺ T cells isolated from HC PBMCs, then activated with anti-CD3 and anti-CD28 mAbs for 24 h followed by further 48-h culture with lactate alone or in the presence of SLC5A12 Ab, or left untreated, in medium containing low glucose (5 mM) and 5% FBS (n = 3, each in duplicate). (B) NAD⁺ and NADH intracellular levels in CD4⁺ T cells (n = 2) treated with sodium lactate (10 mM) for the indicated time points after 72-h activation and shown as NAD⁺/NADH ratio. Lactate-untreated CD4⁺ T cells (CN, dotted line) set to 1. (C) Seahorse measurements of extracellular acidification (left) and oxygen consumption (right) rates (ECAR and OCR, respectively) by 12-h-activated CD4⁺ T cells (n = 3, technical replicates). 1 h prior to the experiment, cells were seeded in a 96-well microplate in XF Assay medium in the presence of 10 mM of glucose. Sodium lactate (10 mM) or PBS was injected during measurement. Data representative of n = 2 independent experiments. (D and E) ¹³C tracing of [U¹³C]-lactate into pyruvate and citrate. Activated CD4⁺ T cells were incubated for 48 h with [U¹³C]-lactate in the presence or absence of SLC5A12 Ab in medium containing low glucose (5 mM) and 5% FBS (n = 2, each in duplicate). Polar metabolites were extracted, analyzed by LC-MS and peak areas of mass isotopologues normalized to cell number are represented. (F and G) Acetyl-CoA (F) and citrate (G) intracellular levels in CD4⁺ T cells (n = 3) treated with sodium lactate (10 mM) for the indicated time points after 72-h activation. Lactate-untreated CD4⁺ T cells (CN, dotted line) set to 1. Two tailed Student’s t test. Data expressed as mean ± SEM. ^∗p ≤ 0.05; ^∗∗p ≤ 0.01; ^∗∗∗p ≤ 0.001.

**Figure 3**
Lactate Shapes the Effector Phenotype of CD4⁺ T Cells at the Site of Inflammation via SLC5A12 (A) Relative mRNA expression levels of *IL17A*, *IL22*, *IFNγ*, *IL6*, *IL10*, and *TGFβ* as assessed by qRT-PCR in tonsil CD4⁺ T cells treated with sodium lactate (10 mM) and/or SLC5A12 Ab or left untreated (n = 5). Levels of mRNA of each cytokine expressed by lactate-untreated CD4⁺ T cells were set to 1 (CN, dotted line). (B) IL-17A and IFNγ ELISAs from supernatants of tonsil CD4⁺ T cells treated as in (A), (n = 5, each in duplicate). (C) Relative mRNA expression levels of *RORγT*, *FOXO1*, *FOXP3*, *PD1*, *CXCR5*, and *BCL6* as assessed by qRT-PCR in tonsil CD4⁺ T cells treated as in (A), (n = 5). Levels of mRNA of each cytokine expressed by lactate-untreated CD4⁺ T cells set to 1 (CN, dotted line). (D) Representative flow cytometry plots of CD4⁺IL17⁺, CD4⁺FOXP3⁺, CD4⁺PD1⁺CXCR5⁺, CD4⁺IFNγ⁺, and CD4⁺IL10⁺ tonsil CD4⁺ T cells incubated in the presence or absence of SLC5A12 Ab (left; n = 3). Quantification bar charts (right). (E) Percentage of IFNγ⁺, IL17A⁺, IL21⁺, Treg (CD25⁺Foxp3⁺), and cytokine-negative (Neg CKS; left) or RORγt⁺, Treg (CD25⁺Foxp3⁺), Tfh (CXCR5⁺PD-1⁺ICOS⁺), and Tbet⁺ (right) CD4⁺SLC5A12⁺ T cell subsets in 48-h activated human HC PBMCs (n = 5). Two-tailed Student’s t test. Data expressed as mean ± SEM. ^∗p ≤ 0.05; ^∗∗p ≤ 0.01; ^∗∗∗p ≤ 0.001.

**Figure 4**
Lactate Induces IL17 via Nuclear PKM2- and FAS-Mediated STAT3 Phosphorylation CD4⁺ T cells were isolated from HC PBMCs and activated with anti-CD3 and anti-CD28 mAb. (A) ROS levels in CD4⁺ T cells (n = 3) treated with sodium lactate (10 mM) for the indicated time points after 72-h activation. PBS and H₂O₂ were used as negative and positive control, respectively. (B) Representative western blots showing nuclear PKM1/2, P-STAT3, STAT3, and cytosolic PKM1/2 in activated CD4⁺ T cells treated with sodium lactate (10 mM) for the indicated time points or left untreated (CN). Histone H3 and β-actin were used as controls for nuclear and cytosolic fraction, respectively. Data representative of n = 3 independent experiments. (C) Representative western blots (left) and densitometric quantification (right; n = 3) of P-STAT3, STAT3, P-STAT1, and STAT1 expression by activated CD4⁺ T cells treated with sodium lactate (10 mM) and/or SLC5A12 Ab, or left untreated. Untreated CD4⁺ T cells (CN, dotted line) set to 1. (D) Representative western blots (left) and densitometric quantification (right; n = 3) of P-ACC, ACC, P-AMPK, and AMPK expression by activated CD4⁺ T cells treated with sodium lactate (10 mM) for the indicated time points or left untreated (CN). Untreated CD4⁺ T cells (CN, dotted line) set to 1. (E) Representative western blots showing cytosolic and mitochondrial P-ACC and ACC in activated CD4⁺ T cells treated with sodium lactate (10 mM) for the indicated time points or left untreated (CN). β-actin and VDAC were used as controls for cytosolic and mitochondrial fraction, respectively. Data representative of n = 2 independent experiments. (F) Mass spectrometry carbon tracer analysis of palmitate in 48-h [U¹³C]-lactate-fed activated CD4⁺ T cells treated as in Figure 2D (n = 4, time points 0, 24, and 48 h; n = 2, time points 72 and 96 h). (G) Representative western blots (left) and densitometric quantification (right; n = 2) of P-STAT3 and STAT3 expression by activated CD4⁺ T cells treated with sodium lactate (10 mM) alone or in combination with C75 (10 μM), TOFA (20 μM), and DHEA (20 μM) or left untreated (CN). Untreated CD4⁺ T cells (CN, dotted line) set to 1. (H) IL-17A and IFNγ ELISAs from supernatants of activated CD4⁺ T cells treated with sodium lactate (10 mM) alone or in combination with C75 (10 μM), TOFA (20 μM), DHEA (20 μM), DASA (20 μM), AICAR (1 mM), or left untreated (n = 5, each in duplicate; for lactate + DASA + C75 or lactate + DASA + TOFA, n = 2, each in duplicate). (I) Representative western blots (left) and densitometric quantifications (right; n = 3) of P-ACC, ACC, P-STAT3, and STAT3 expression by activated CD4⁺ T cells from Slc5a12 WT or KO mice, treated with sodium lactate (10 mM) or left untreated (CN). Also, IL-17A ELISA from supernatants of activated CD4⁺ T cells from Slc5a12 WT or KO mice, treated with sodium lactate (10 mM) or left untreated (n = 3, each in duplicate). Two-tailed Student’s t test (A), (C), (F), (H), and (I) or one-way ANOVA (G). Data expressed as mean ± SEM. ∗p ≤ 0.05; ∗∗p ≤ 0.01; ∗∗∗p ≤ 0.001; ###p ≤ 0.001 versus lactate (H). (J) Schematic depicting the described findings: lactate modulates IL17 expression by activating two pathways, PKM2 translocation into the nucleus and FAS induction, converging on STAT3-induced transcription of IL17. See also Figure S4.

**Figure 5**
SLC5A12 Blockade Promotes the Egress of CD4⁺ T Cell from the Inflamed Tissue (A) Organ culture schematic describing the analysis performed to assess the egress of mononuclear cells (MCs) from the inflamed tissue. (B) Analysis of MCs (CD4⁺, CD8⁺, CD19⁺, and CD14⁺) egress from tonsil tissues (n = 3, each in duplicate) cultured with sodium lactate (10 mM) and/or SLC5A12 Ab, or left untreated. Untreated MCs (CN, dotted line) set to 100. (C and D) Representative flow cytometry plots (D) and quantification (E) of egressed CD4⁺ T cells from RA synovial tissues (n = 3) cultured with sodium lactate (10 mM) and/or SLC5A12 Ab, 3C7 mAb, 10E11 mAb, or left untreated. Untreated MCs (CN, dotted line) set to 100. Two-tailed Student’s t test. Data expressed as mean ± SEM. ∗p ≤ 0.05; ∗∗p ≤ 0.01; ∗∗∗p ≤ 0.001. See also Figure S5.

**Figure 6**
Lactate Reduces the Motility of CD4⁺ T Cells via Reduced Glycolysis and Enhanced FAS (A) Representative western blots (left) and densitometric quantification (right; n = 3) of HK1, HK2, PFK, enolase 1α, and PKM1/2 expression by activated CD4⁺ T cells treated with sodium lactate (10 mM), or left untreated. Untreated CD4⁺ T cells (CN, dotted line) set to 1. (B) Representative western blots (left) and densitometric quantification (right; n = 3) of HK1, HK2, enolase 1α, PKM1/2, GCK, and aldolase expression by activated CD4⁺ T cells treated with sodium lactate (10 mM) and/or SLC5A12 Ab, or left untreated. Untreated CD4⁺ T cells (CN, dotted line) set to 1. (C) Representative western blots showing mitochondrial and cytosolic HK2 in activated CD4⁺ T cells treated with sodium lactate (10 mM) for the indicated time points or left untreated (CN). VDAC and β-actin were used as controls for mitochondrial and cytosolic fraction, respectively. Data representative of n = 2 independent experiments. (D) Representative immunofluorescence images of untreated and lactate-treated CD4⁺ T cells. Co-staining for hexokinase 2 (green), MitoTracker (red), and DAPI (blue). Scale bar, 10 μm. (E) NADP⁺ and NADPH intracellular levels in CD4⁺ T cells (n = 5) treated with sodium lactate (10 mM) for the indicated time points after 72-h activation and shown as NADP⁺/NADPH ratio. Lactate-untreated CD4⁺ T cells (CN, dotted line) set to 1. (F) *In vitro* chemokinesis of activated CD4⁺ T cells in response to CCL20 (500 ng/mL; n = 4) or CXCL10 (300 ng/mL; n = 3) in the presence of sodium lactate (10 mM) with or without the metabolic drugs C75 (10 μM), TOFA (20 μM), and DHEA (20 μM). Untreated CD4⁺ T cells (w/o CXCL10, dotted line) were set to 100. (G) *In vitro* chemokinesis of activated CD4⁺ T cells (n = 4) from Slc5a12 WT or KO mice in response to CXCL10 (300 ng/mL; 4 h) in the presence of sodium lactate (10 mM). Untreated CD4⁺ T cells (CN, dotted line) were set to 100. Two-tailed Student’s t test (A), (B), and (E) or one-way ANOVA (F) and (G). Data expressed as mean ± SEM. ∗p ≤ 0.05; ∗∗p ≤ 0.01; ∗∗∗p ≤ 0.001; #p ≤ 0.05 versus lactate + chemokine. See also Figure S6.

**Figure 7**
SLC5A12 Expression Correlates with RA Disease Activity and Its Blockade Improves Clinical Scores in a Murine Model of (CD4⁺ T Cells Joint-Enriched) Arthritis (A) Heatmap showing RNA-sequencing expression of groups of metabolic genes differentially expressed (FDR < 0.05) between synovial biopsies (n = 87) from early rheumatoid arthritis. Synovial biopsies were classified as positive or negative for ectopic lymphoid structures (ELS) by histological analysis. Upper tracks show synovial histology inflammatory score (Krenn score), expression level of cell-lineage CD4⁺ T cell gene modules, ELS histology grouping and overall histology pathotype (lymphoid, myeloid or fibroid). (B) Synovium SLC5A12 transcript positively correlates with delta disease activity score (Δ DAS28-CRP) calculated as the difference between DAS28-CRP at baseline and DAS28-CRP at 6 months and FASN transcript; also shown is the positive correlation between the inflammatory score DAS28-CRP with IL17RA transcript (n = 87). Correlation analyses performed using Spearman's correlation coefficients. (C–F) Arthritis score in mice treated with the indicated antibodies versus controls. Arrows indicate days at which antibodies were injected. A score of 0 indicates no clinical signs of arthritis; a score of 1 for each of the toes, pad, and ankle indicates swelling and redness. Maximum score for each paw is 7 (n = 6 per group; C). Representative images of the paws at day 21 post-immunization showing the effects (i.e., swelling and redness) of treatment with SLC5A12 Ab as compared to the SLC5A12 isotype control antibody (D). Histological score in pads of mice subjected to different treatments, as shown (each dot corresponds to the assessment of an H&E slide acquired from the representative group, n = 19–24 slides/group; E). IHC with haematoxylin counterstain showing immune infiltrate (arrows) in the pad of mice treated with SLC5A12 Ab as compared to isotype control antibody-treated mice (F). Two-tailed Student’s t test (C) and (E). Data represent mean ± SD. ∗p ≤ 0.05; ∗∗p ≤ 0.01; #p ≤ 0.05. See also Figure S7.

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Comment in

Lactate rewires synovial T cells in RA.
Clarke J. Clarke J. Nat Rev Rheumatol. 2020 Jan;16(1):4. doi: 10.1038/s41584-019-0344-1. Nat Rev Rheumatol. 2020. PMID: 31772291 No abstract available.

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Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4⁺ T Cell Metabolic Rewiring

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Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4⁺ T Cell Metabolic Rewiring

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