. 2017 Jun 15;169(7):1263-1275.e14.

doi: 10.1016/j.cell.2017.05.031.

Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Affiliations

¹ Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany.
² Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
³ Language and Information Engineering Laboratory, Friedrich-Schiller-University, 07743 Jena, Germany.
⁴ INSERM U1213, Université Claude Bernard Lyon, 69100 Villeurbanne, France.
⁵ Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany.
⁶ Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. Electronic address: mpsoares@igc.gulbenkian.pt.

PMID: 28622511
PMCID: PMC5480394
DOI: 10.1016/j.cell.2017.05.031

Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Sebastian Weis et al. Cell. 2017.

. 2017 Jun 15;169(7):1263-1275.e14.

doi: 10.1016/j.cell.2017.05.031.

Authors

Affiliations

¹ Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany.
² Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
³ Language and Information Engineering Laboratory, Friedrich-Schiller-University, 07743 Jena, Germany.
⁴ INSERM U1213, Université Claude Bernard Lyon, 69100 Villeurbanne, France.
⁵ Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany.
⁶ Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. Electronic address: mpsoares@igc.gulbenkian.pt.

PMID: 28622511
PMCID: PMC5480394
DOI: 10.1016/j.cell.2017.05.031

Abstract

Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.

Keywords: disease tolerance; ferritin; gluconeogenesis; glucose-6-phosphatase; heme; infection; inflammation; iron; metabolism; sepsis.

PubMed Disclaimer

Figures

**Figure 1**
FTH Establishes Disease Tolerance to Sepsis (A) FTH western blot from C57BL/6 mice liver extracts before (Control; Ctr) or 12 hr after a severe CLP. Representative western blot from one out of three mice per genotype. (B) Densitometry of FTH protein expression normalized to β-actin. Data pooled from three mice per genotype. (C) Representative immunostaining of liver FTH (green), DNA (blue), and F4/80⁺ Kupffer cells (red) before (Control; Ctr) or 12 hr after a severe CLP. (D) FTH western blot in liver extracts from *Fth*^lox/lox and *Mx1*^CreFth^Δ/Δ mice before (Control; Ctr) and 48 hr after CLP. Representative of four mice per genotype. (E) Survival of *Fth*^lox/lox (n = 20) and *Mx1*^CreFth^Δ/Δ (n = 17) mice subjected to CLP, pooled from four independent experiments. (F) Aerobic (Ae) and anaerobic (An) bacterial colony forming units (CFU), 48 hr after CLP. Data pooled from three independent experiments. (G) Survival after CLP in bone marrow chimeric mice expressing *Fth* in all tissues (*Fth*^+/+ → *Fth*^+/+, n = 14), in parenchyma only (*Fth*^Δ/Δ → *Fth*^+/+, n = 14), or in bone marrow-derived cells only (*Fth*^+/+ → *Fth*^Δ/Δ, n = 8). Data from three independent experiments with similar trend. (H) Survival of control *Fth*^lox/lox mice (n = 35), *Alb*^CreFth^Δ/Δ (n = 12), *LysM*^CreFth^Δ/Δ (n = 24), and *Alb*^CreLysM^CreFth^Δ/Δ (n = 12) mice lacking FTH expression in hepatocytes, myeloid cells, or hepatocytes and myeloid cells, respectively. Data pooled from ten independent experiments. (I and J) Clinical severity score (CSS) (Gonnert et al., 2011) (I) and survival of *Fth*^lox/lox (n = 6) and *Mx1*^CreFth^Δ/Δ (n = 4) mice subjected to PCI (J). Data for CSS is from one independent experiment and survival is from two independent experiments. (K) CFU for aerobic (Ae) and anaerobic (An) bacteria 24 hr after PCI in two independent experiments. Red bars in (F) and (K) are mean values and dotted circles are individual mice. PC, peritoneal cavity. ^∗p < 0.05; ^∗∗p < 0.01; ^∗∗∗p < 0.001. See also Figures S1, S2, and S3.

**Figure S1**
FTH Establishes Disease Tolerance to Sepsis, Related to Figure 1 (a) Representative FTH immunostaining in the liver of C57BL/6 mice before (Control) and 12 hr after severe CLP. Red: F4/80⁺ Kupffer cells; Green: FTH, Blue: DNA. (b) Control staining with secondary antibodies only. (c) Quantification of *Fth* mRNA by qRT-PCR before (Control; Ctr.) and 12 hr after CLP. Data are shown as mean ± SD of 3 mice per group. (d) Percentage of circulating CD45.1⁺ versus CD45.2⁺ leukocytes in control (*Fth*^+/+→*Fth*^+/+), (*Fth*^+/+→*Fth*^Δ/Δ) and (*Fth*^Δ/Δ→*Fth*^+/+) bone marrow chimeras. (e) Percentage of CD19⁺ B cells, TCRβ⁺ T cells, Gr1⁺CD11b^high PMN cells and CD11b⁺ (monocyte/macrophages and PMN cells) in the same mice as in (d). Data in (d) and (e) is shown as mean ± SD of 4-6 mice per group, pooled from 2-3 representative experiments. (f) *Fth* mRNA expression quantified by qRT-PCR in circulating leukocytes and expressed as % relative to (B6→B6) controls. Data shown as mean ± SD of 3-4 mice per group, pooled from 2-3 representative experiments. ^∗p < 0.05.

**Figure S2**
FTH Does Not Modulate Cytokine Levels or Tissue Damage, Related to Figure 1 (a) Cytokine levels in plasma 24 hr after CLP. Mean ± SD (n = 4 per genotype). (b) Serological markers before (Control; Ctrl) and 48 hr after CLP. Mean ± SD, n = 3-5 mice per genotype, pooled from 3 independent experiments. (c) H&E stained paraffin sections representative of at least three *Fth*^lox/lox and *Mx1*^CreFth^Δ/Δ mice untreated (Control) and 48 hr after CLP. B: bronchus; CV: central vein; G: glomerulus. Magnification 400x.

**Figure S3**
FTH Does Not Modulate Cardiovascular Function, Related to Figure 1 (a) H&E stained paraffin section of hearts from *Fth*^lox/lox and *Mx1*^CreFth^Δ/Δ mice before and 48 hr after CLP. Images are representative of at least 3 mice per genotype per experimental conditions. Magnifications are 100 (top) and 400x. (b) Cardiac pressure-volume (PV) loop analysis of *Fth*^lox/lox and *Mx1*^CreFth^Δ/Δ mice, 48 hr after CLP. Load-dependent, *i.e.* Heart rate (HR) end-systolic pressure (ESP), cardiac output (CO), relaxation (Tau-Glantz), pressure volume area (PVA) and mean arterial pressure (MAP) and load-independent, *i.e.* slope of end-systolic pressure volume Relationship (ESPVR) and maximum of generated energy (E_max) parameters are shown as mean ± SD from n = 3-6 mice per group pooled from 4 independent experiments. NS: non-significant. (c) Vascular leakage monitored by quantification of Evans Blue accumulation in parenchyma organs, before and 48 hr after CLP. Data are shown as mean ± SD from n = 5 mice per group, pooled from 3 independent experiments. NS: non-significant.

**Figure 2**
FTH Regulates Glucose Metabolism in Response to Polymicrobial Infection (A–C) Relative weight (A), temperature (B), and blood glucose levels (C) in *Fth*^lox/lox (n = 13) and *Mx1*^CreFth^Δ/Δ (n = 15) mice subjected to CLP. Mean ± SEM from five independent experiments. (D) Blood glucose levels in *Mx1*^CreFth^Δ/Δ mice subjected to CLP and receiving glucose (n = 15) (gavage; 2 mg/kg body weight [BW]; two times daily for 4 days and one time daily for 3 days) or vehicle (n = 12). Mean ± SEM from three independent experiments. (E) Survival of the same mice as in (D). (F) CFU for aerobic (Ae) and anaerobic (An) bacteria, 48 hr after CLP. Red bars represent mean values and dotted circles individual mice. (G) Blood glucose levels in C57BL/6 mice receiving heme (n = 15) (intraperitoneally [i.p.] 30 mg/kg BW) or control protoporphyrin IX (PPIX) (n = 10). Mean ± SEM from three to five independent experiments. (H) Blood glucose levels in *Fth*^lox/lox (n = 8) and *Mx1*^CreFth^Δ/Δ (n = 9) mice receiving heme (i.p. 25–30 mg/kg BW). Mean ± SD from two independent experiments. (I) Survival of *Fth*^lox/lox (n = 8) and *Mx1*^CreFth^Δ/Δ (n = 9) mice receiving heme (i.p. 25–30 mg/kg BW). (J) Blood glucose levels in C57BL/6 *Tlr4*^+/+ (n = 13) and *Tlr4*^−/− (n = 9) mice receiving heme (i.p. 30 mg/kg BW). Mean ± SEM from three to four independent experiments. (K) Blood glucose levels in C57BL/6 *Ifnr1*^+/+ (n = 7) and *Ifnr1*^−/− (n = 7) mice receiving heme (i.p. 30 mg/kg BW). Mean ± SD from two independent experiments. PC, peritoneal cavity. Numbers in gray in (A)–(D) and (H) are live/total mice at each time point. ^∗p < 0.05; ^∗∗p < 0.01. See also Figure S4.

**Figure S4**
FTH Expression and Glucose Metabolism, Related to Figure 2 (a) Food intake in *Fth*^lox/lox and *Mx1*^CreFth^Δ/Δ mice before and after CLP. Data are shown as mean and SD from 3 mice per genotype. (b) Blood glucose levels in *Fth*^lox/lox (n = 3) and *Mx1*^CreFth^Δ/Δ (n = 3) mice in the first 12 hr after CLP. Mean ± SD, data from 1 experiment. (c) Blood glucose levels in C57BL/6 mice in the first 12 hr after CLP (n = 7) or control sham operation (n = 12). Mean ± SD, data from 3-4 independent experiments. (d) Total heme levels in the peritoneal cavity in C57BL/6 mice before (n = 4) and 3 hr after CLP (n = 3). (e) Blood glucose levels in C57BL/6 mice in the first 8 hr after heme (n = 15) or protoporphyrin IX (PPIX) (n = 10) administration (*i.p.*; 30 mg/kg BW). Mean ± SEM, data from 3-5 independent experiments. (f) Blood glucose levels in *Fth*^lox/lox (n = 8) and *Mx1*^CreFth^Δ/Δ (n = 9) in the first 8 hr after heme administration (*i.p.*; 25 to 30 mg/kg BW). Mean ± SD from 2 independent experiments. (g) Blood glucose levels in C57BL/6 *Tlr4*^+/+ (n = 13) and *Tlr4*^−/− (n = 9) mice in the first 8 hr after heme administration (*i.p.*; 30 mg/kg BW). Mean ± SEM from 3-4 independent experiments. (h) Blood glucose levels in C57BL/6 *Ifnr1*^+/+ (n = 7) and *Ifnr1*^−/− (n = 7) mice in the first 8 hr after heme administration (*i.p.*; 30 mg/kg BW). Mean ± SD from 2 independent experiments. (i) Oral glucose tolerance test (oGTT), (j) pyruvate tolerance test (PTT) and (k) glucagon challenge test (GCT) in *Fth*^lox/lox and *Mx1*^CreFth^Δ/Δ mice. Data are shown as mean ± SEM, pooled from 3 independent experiments with n = 3 mice per genotype per experiment. (l) insulin tolerance test (ITT) in *Fth*^lox/lox and *Mx1*^CreFth^Δ/Δ mice. Data are shown as mean ± SD, from 1 experiment with n = 5 mice per genotype. (m) Plasma insulin levels in *Fth*^lox/lox and *Mx1*^CreFth^Δ/Δ mice after overnight fasting. Data are shown as mean ± SD from 4-5 mice per genotype. (n) Plasma insulin levels in *Fth*^lox/lox and *Mx1*^CreFth^Δ/Δ mice before (control; Ctr.) and 48 hr after CLP. Data are shown as mean ± SD from 4-6 mice per genotype, pooled from 2-3 experiments.

**Figure 3**
FTH Prevents Liver Glucose Metabolism from Shifting Toward Glycolysis in Detriment of Gluconeogenesis (A) Blood glucose in *Mx1*^CreFth^Δ/Δ mice subjected to CLP and receiving pyruvate (n = 6) or vehicle (n = 7). Mean ± SD from two independent experiments. Numbers in gray indicate live/total mice at different time points. (B) Survival of the same mice as in (A). (C) Targeted metabolomics of the liver and flux balance analysis for ATP generation using data integration into a reconstructed metabolic network iMM1415 (Sigurdsson et al., 2010). Data are shown as mean ± SD (n = 5 mice per group). DHAP, dihydroxyacetone phosphate; F6P, fructose 6-phosphate; F16P, fructose-1,6-bisphosphate; GAP, glyceraldehyde 3-phosphate; G6P, glucose 6-phosphate; 13bPG, 1,3-bisphosphoglycerate; 2PG, 2-phosphoglycerate; 3PG, 3-phosphoglycerate; PEP, phosphopyruvate. ^∗p < 0.05; ^∗∗p < 0.01; ^∗∗∗p < 0.001. See also Figure S5 and Tables S1 and S2.

**Figure S5**
Targeted Amino Acids Metabolomics of the Liver, Related to Figure 3 Data are shown as mean ± SD of 5 mice per group. ^∗p < 0.05; ^∗∗p < 0.01; ^∗∗∗p < 0.001. NS: non-significant.

**Figure 4**
FTH Sustains Hepatic G6Pase in Response to Systemic Polymicrobial Infection (A) Volcano plot of mean RNA expression from RNA microarray screen in the liver of *Mx1*^CreFth^Δ/Δ versus *Fth*^lox/lox mice, 48 hr after CLP (n = 4 mice per group). (B) Validation of *G6pc1* mRNA expression by qRT-PCR in the liver of *Mx1*^CreFth^Δ/Δ mice not subjected to CLP (n = 13), 48 hr after CLP (n = 12) versus *Fth*^lox/lox mice not subjected to CLP (n = 11), or 48 hr after CLP (n = 11). Data pooled from three independent experiments. (C and D) Representative western blot of G6pc1 in *Mx1*^CreFth^Δ/Δ versus *Fth*^lox/lox mice (C) and relative quantification by densitometry (D) before (Control; Ctr) or 48 hr after CLP (n = 6 per group). (E) Quantification of liver *Gpt1* mRNA by qRT-PCR, same mice as (B). (F) Liver G6Pase enzymatic activity, same mice as (B). (G) Quantification of *G6PC1* mRNA levels by qRT-PCR in HepG2 cells untreated (−) or treated (+) with heme and/or TNF. Mean ± SEM from eight independent experiments with similar trend. (H) G6PC1 protein levels in HepG2 cells treated as in (G). (I) Relative quantification G6PC1 protein levels by densitometry of western blot from HepG2 cells treated as in (G) and (H). (J) Relative luciferase units (RLU) in HepG2 cells transiently co-transfected with a rat *G6pc1* firefly luciferase and CMV *Renilla* luciferase reporters. Control cells were transfected with a promoterless firefly luciferase reporter. Cells were treated, 48 hr after transfection, with heme and TNF. Data are shown as mean RLU ± SD from four independent experiments with similar trend. (K) Liver mRNA quantification by qRT-PCR in C57BL/6 mice receiving heme (+; n = 8) (i.p. 30 mg/kg BW) or not (−; n = 9). Data pooled from three independent experiments. (L) Liver mRNA quantification by qRT-PCR in *Mx1*^CreFth^Δ/Δ versus *Fth*^lox/lox mice receiving heme (+; i.p. 15 mg/kg BW; n = 3 per genotype) or not (−; n = 6–8 per genotype). Data pooled from one to three independent experiments. (M) Relative luciferase units (RLU) in HepG2 cells transiently co-transfected with a rat *G6pc1* firefly luciferase and a CMV *Renilla* luciferase reporters plus a human FTH expression vector. Cells transfected with a promoterless firefly luciferase reporter were used as baseline RLU. Transfected cells were treated 48 hr thereafter with heme and TNF and analyzed 12 hr thereafter. Data shown as mean RLU ± SD from five independent experiments with similar trend. Red bars in (B), (D)–(F), (J), and (K) represent mean values and doted circles indicate individual mice. ^∗p < 0.05; ^∗∗p < 0.01; ^∗∗∗p < 0.01. See also Figure S6.

**Figure S6**
Liver Gluconeogenesis Is Required to Establish Disease Tolerance to Sepsis, Related to Figures 4 and 5 (a) Western Blot of G6PC1 and p21 in HepG2 cells untreated (-) or treated (+) with heme and TNF in the presence (+) or absence (-) of Lactacystin (Lact.) or MG132. Actin was used as loading control. Data are representative of three independent experiments with the same trend. (b) G6Pase enzymatic activity in HepG2 cells transduced (+) or not (-) with a G6PC1 Rec.Ad. and when indicated (+) co-transduced with a FTH Rec.Ad. Transduction with a LacZ Rec. Ad. was used as a control. NT: Not transduced. Cells were treated (+) or not (-) with heme and TNF 72 hr after Rec.Ad. transduction. Data are shown as mean ± SD, pooled from 2 independent experiments with four replicates each. (c) Temperature and (d) weight of *G6pc1*^lox/lox (n = 12) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 12) mice subjected to CLP. Data are shown as mean ± SEM, pooled from 3 independent experiments. (e) Blood glucose and (f) clinical severity score in Control (C57BL/6; n = 7) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 5) mice subjected to CLP. Mean ± SD pooled from 2 independent experiments. (g) Serological markers of organ injury in C57BL/6 (n = 7) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 5) mice 6 hr mice after CLP. (h) H&E stained paraffin sections representative of at least four *G6pc1*^lox/lox and *Alb*^CreER^T2G6pc1^Δ/Δ mice 9 hr after PCI. B: bronchus; CV: central vein; G: glomerulus. Magnification 400x. (i) Temperature and (h) weight and (j) blood glucose levels in *G6pc1*^lox/lox (n = 6) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 7) mice receiving heme (*i.p*; 30 mg/kg BW). Mean ± SD from 2 independent experiments. ^∗p < 0.05; ^∗∗p < 0.01; ^∗∗∗p < 0.001.

**Figure 5**
Liver Gluconeogenesis Is Critical to Establish Disease Tolerance to Sepsis (A) G6pc1 protein expression in the liver of control (*G6pc1*^lox/lox; Ctr) and *Alb*^CreER^T2G6pc1^Δ/Δ (*G6pc1*^Δ/Δ) mice. (B) Blood glucose levels of *G6pc1*^lox/lox (n = 12) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 12) mice subjected to CLP. Data are shown as mean ± SEM from three independent experiments. (C) Survival of control (*G6pc1*^lox/lox; n = 10) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 10) mice subjected to CLP. Data were pooled from two independent experiments with similar trend. (D) Blood glucose of control (C57BL/6; n = 7) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 5) mice subjected to PCI. Data are shown as mean ± SD from two independent experiments with the same trend. (E) Survival of control (C57BL/6; n = 10) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 8) subjected to PCI. Data pooled from three independent experiments with similar trend. (F) CFU for aerobic (Ae) and anaerobic (An) bacteria, 6 hr after PCI. Red bars represent mean values and dotted circles represent individual mice. PC, peritoneal cavity. (G) Blood glucose levels in *G6pc1*^lox/lox (n = 6) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 7) mice receiving heme (i.p. 30 mg/kg BW). Mean ± SD from two independent experiments. (H) Survival of same mice as (G). (I) Blood glucose levels in *G6pc1*^lox/lox (n = 6) and *Alb*^CreER^T2G6pc1^Δ/Δ (n = 9) mice receiving LPS (i.p. 5 mg/kg BW). Mean ± SD from two independent experiments. (J) Survival of same mice as (I). (K) Blood glucose levels in *G6pc1*^lox/lox (n = 9) and *Alb*^CreER^T2Gpc1^Δ/Δ (n = 10) mice receiving poly(I:C) (intra-retro orbital [i.r.o.] 30 mg/kg BW). Mean ± SD from two independent experiments. (L) Survival of same mice as (K). Numbers in gray (B, D, G, I, and K) are live/total mice at each time point. ^∗p < 0.05; ^∗∗p < 0.01. See also Figure S6.

**Figure 6**
FTH Overexpression or Ferritin Administration Induce Disease Tolerance to Sepsis (A) Survival of C57BL/6 mice transduced 48 hr before severe CLP with FTH Rec.Ad. (n = 11), ferroxidase-deficient FTH Rec.Ad. (FTH^m; n = 11), LacZ Rec.Ad. (n = 12), or receiving vehicle (PBS; n = 19). Data pooled from six independent experiments with similar trend. (B) CFU for aerobic (Ae) and anaerobic (An) bacteria, 12 hr after CLP in mice treated as in (A). (C) Representative western blot in HepG2 cells transduced with LacZ, FTH, or mutated FTH (FTH^m) Rec.Ad. (D and E) Densitometry of G6PC1 (D) and FTH protein (E) expression normalized to α-tubulin (n = 4 per group). (F) Expression of *G6pc1* mRNA quantified by qRT-PCR in HepG2 cells exposed (+) or not (−) to heme, TNF, and deferoxamine (DFO). Mean ± SEM from three independent experiments done in duplicates. (G) Survival of C57BL/6 mice receiving apoferritin (n = 16), ferritin (n = 10), BSA (n = 12), or saline (n = 12), 24 hr before severe CLP. Data pooled from five independent experiments. (H) CFU for aerobic (Ae) and anaerobic (An) bacteria 12 hr after severe CLP in mice treated as in (G). Data from three independent experiments. (I) Survival of C57BL/6 mice receiving apoferritin (n = 22), BSA (n = 20), or saline (n = 16) 6 hr after severe CLP. Data pooled from seven independent experiments. Red bars represent mean values and dotted circles represent individual mice (B and G). PC, peritoneal cavity; NS, non-significant. ^∗p < 0.05, ^∗∗p < 0.01. See also Figure S7.

**Figure S7**
FTH Overexpression and Apo-Ferritin Administration Induce Disease Tolerance to Sepsis, Related to Figure 6 (a) Serological markers of organ injury, before (Control; Ctr) and 12 hr after severe CLP in C57BL/6 mice transduced with Rec.Ad. encoding FTH, ferroxidase-deficient FTH (FTH^m), LacZ or receiving vehicle (PBS). Data are shown as mean ± SD from n = 4-5 mice per group, pooled from 3 independent experiments. (b) Serological markers of organ injury, before (Control; Ctr) and 12 hr after severe CLP C57BL/6 mice receiving apoferritin, ferritin, bovine serum albumin (BSA) or saline. Data are shown as mean ± SD from n = 4-5 mice per group, samples were pooled from 3 independent experiments. ^∗p < 0.05, ^∗∗p < 0.01; ^∗∗∗∗p < 0.001.

**Figure 7**
Antioxidants Bypass the Requirement of FTH in the Establishment of Normoglycemia and Disease Tolerance to Sepsis (A–C) Relative weight (A), blood glucose (B), and survival (C) of *Mx1*^CreFth^Δ/Δ mice subjected to CLP and receiving NAC (n = 7; 15 mg/kg) or vehicle (n = 6). Data pooled from two independent experiments. (D) Colony forming units (CFU) for aerobic (Ae) and anaerobic (An) bacteria, 48 hr after CLP. PC, peritoneal cavity. Red bars represent mean values and doted circles represent individual mice. Pooled from two independent experiments. (E) Expression of *G6PC1* mRNA quantified by qRT-PCR in HepG2 cells exposed (+) or not (−) to heme, TNF, and/or NAC. Data shown as mean ± SD from four independent experiments. (F and G) Blood glucose (F) and survival (G) of *Mx1*^CreFth^Δ/Δ mice subjected to CLP and receiving BHA (n = 11; 50 mg/kg) or vehicle (n = 9). Data shown as mean ± SD. Pooled from three independent experiments. (H–J) Relative weight (H), blood glucose (I), and survival (J) of *Alb*^CreER^T2G6pc1^Δ/Δ mice subjected to CLP and receiving NAC (n = 5) or vehicle (n = 5). Mean ± SD from one experiment. NS, non-significant. ^∗p < 0.05, ^∗∗p < 0.01. Numbers in gray (A, B, F, I, and J) indicate live/total mice.

See this image and copyright information in PMC

Comment in

Just a Spoonful of Sugar Helps the Tolerance Go Up.
Chervonsky AV. Chervonsky AV. Cell. 2017 Jun 15;169(7):1170-1172. doi: 10.1016/j.cell.2017.05.040. Cell. 2017. PMID: 28622502

Cited by

TANK Binding Kinase 1 Promotes BACH1 Degradation through Both Phosphorylation-Dependent and -Independent Mechanisms without Relying on Heme and FBXO22.
Liu L, Matsumoto M, Watanabe-Matsui M, Nakagawa T, Nagasawa Y, Pang J, Callens BKK, Muto A, Ochiai K, Takekawa H, Alam M, Nishizawa H, Shirouzu M, Shima H, Nakayama K, Igarashi K. Liu L, et al. Int J Mol Sci. 2024 Apr 9;25(8):4141. doi: 10.3390/ijms25084141. Int J Mol Sci. 2024. PMID: 38673728 Free PMC article.
Epirubicin for the Treatment of Sepsis and Septic Shock (EPOS-1): study protocol for a randomised, placebo-controlled phase IIa dose-escalation trial.
Thomas-Rüddel D, Bauer M, Moita LF, Helbig C, Schlattmann P, Ehler J, Rahmel T, Meybohm P, Gründling M, Schenk H, Köcher T, Brunkhorst FM, Gräler M, Heger AJ, Weis S; EPOS-1 study group; SepNetCriticalCare TrialsGroup. Thomas-Rüddel D, et al. BMJ Open. 2024 Apr 22;14(4):e075158. doi: 10.1136/bmjopen-2023-075158. BMJ Open. 2024. PMID: 38653508 Free PMC article.
Ferritin heavy chain supports stability and function of the regulatory T cell lineage.
Wu Q, Carlos AR, Braza F, Bergman ML, Kitoko JZ, Bastos-Amador P, Cuadrado E, Martins R, Oliveira BS, Martins VC, Scicluna BP, Landry JJ, Jung FE, Ademolue TW, Peitzsch M, Almeida-Santos J, Thompson J, Cardoso S, Ventura P, Slot M, Rontogianni S, Ribeiro V, Domingues VDS, Cabral IA, Weis S, Groth M, Ameneiro C, Fidalgo M, Wang F, Demengeot J, Amsen D, Soares MP. Wu Q, et al. EMBO J. 2024 Apr;43(8):1445-1483. doi: 10.1038/s44318-024-00064-x. Epub 2024 Mar 18. EMBO J. 2024. PMID: 38499786 Free PMC article.
Reframing sepsis immunobiology for translation: towards informative subtyping and targeted immunomodulatory therapies.
Shankar-Hari M, Calandra T, Soares MP, Bauer M, Wiersinga WJ, Prescott HC, Knight JC, Baillie KJ, Bos LDJ, Derde LPG, Finfer S, Hotchkiss RS, Marshall J, Openshaw PJM, Seymour CW, Venet F, Vincent JL, Le Tourneau C, Maitland-van der Zee AH, McInnes IB, van der Poll T. Shankar-Hari M, et al. Lancet Respir Med. 2024 Apr;12(4):323-336. doi: 10.1016/S2213-2600(23)00468-X. Epub 2024 Feb 23. Lancet Respir Med. 2024. PMID: 38408467 Free PMC article. Review.
Prevention of lipid droplet accumulation by DGAT1 inhibition ameliorates sepsis-induced liver injury and inflammation.
Teixeira L, Pereira-Dutra FS, Reis PA, Cunha-Fernandes T, Yoshinaga MY, Souza-Moreira L, Souza EK, Barreto EA, Silva TP, Espinheira-Silva H, Igreja T, Antunes MM, Bombaça ACS, Gonçalves-de-Albuquerque CF, Menezes GB, Hottz ED, Menna-Barreto RFS, Maya-Monteiro CM, Bozza FA, Miyamoto S, Melo RCN, Bozza PT. Teixeira L, et al. JHEP Rep. 2023 Dec 11;6(2):100984. doi: 10.1016/j.jhepr.2023.100984. eCollection 2024 Feb. JHEP Rep. 2023. PMID: 38293685 Free PMC article.

See all "Cited by" articles

References

1. Adamzik M., Hamburger T., Petrat F., Peters J., de Groot H., Hartmann M. Free hemoglobin concentration in severe sepsis: methods of measurement and prediction of outcome. Crit. Care. 2012;16:R125. - PMC - PubMed
1. Angus D.C., van der Poll T. Severe sepsis and septic shock. N. Engl. J. Med. 2013;369:2063. - PubMed
1. Berberat P.O., Katori M., Kaczmarek E., Anselmo D., Lassman C., Ke B., Shen X., Busuttil R.W., Yamashita K., Csizmadia E. Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury. FASEB J. 2003;17:1724–1726. - PubMed
1. Clausen B.E., Burkhardt C., Reith W., Renkawitz R., Förster I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 1999;8:265–277. - PubMed
1. Clottes E., Burchell A. Three thiol groups are important for the activity of the liver microsomal glucose-6-phosphatase system. Unusual behavior of one thiol located in the glucose-6-phosphate translocase. J. Biol. Chem. 1998;273:19391–19397. - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

Grants and funding

294709/ERC_/European Research Council/International

LinkOut - more resources

Full Text Sources
Other Literature Sources
- H1 Connect
- scite Smart Citations
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Miscellaneous
- NCI CPTAC Assay Portal
- SciCrunch

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Affiliations

Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Authors

Affiliations

Abstract

Figures

Comment in

Similar articles

Cited by

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous

Abstract

Figures

Comment in

Similar articles

Cited by

References

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous