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Journal of Peking University (Health Sciences) ›› 2022, Vol. 54 ›› Issue (3): 532-540. doi: 10.19723/j.issn.1671-167X.2022.03.020

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Characteristics of amino acid metabolism in myeloid-derived suppressor cells in septic mice

Yuan MA1,Yue ZHANG2,3,Rui LI2,3,Shu-wei DENG2,3,Qiu-shi QIN1,Liu-luan ZHU1,2,3,*()   

  1. 1. Institute of Infectious Diseases, Peking University Ditan Teaching Hospital, Beijing 100015, China
    2. Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
    3. Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
  • Received:2022-01-18 Online:2022-06-18 Published:2022-06-14
  • Contact: Liu-luan ZHU E-mail:zhuliuluan@aliyun.com
  • Supported by:
    the National Natural Science Foundation of China(81871586);the National Natural Science Foundation of China(82172128)

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Abstract:

Objective: To explore the amino acid metabolomics characteristics of myeloid-derived suppressor cells (MDSCs) in mice with sepsis induced by the cecal ligation and puncture (CLP). Methods: The sepsis mouse model was prepared by CLP, and the mice were randomly divided into a sham operation group (sham group, n = 10) and a CLP model group (n = 10). On the 7th day after the operation, 5 mice were randomly selected from the surviving mice in each group, and the bone marrow MDSCs of the mice were isolated. Bone marrow MDSCs were separated to measure the oxygen consumption rate (OCR) by using Agilent Seahorse XF technology and to detect the contents of intracellular amino acids and oligopeptides through ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) technology. Different metabolites and potential biomarkers were analyzed by univariate statistical analysis and multivariate statistical analysis. The major metabolic pathways were enriched using the small molecular pathway database (SMPDB). Results: The proportion of MDSCs in the bone marrow of CLP group mice (75.53% ± 6.02%) was significantly greater than that of the sham group (43.15%± 7.42%, t = 7.582, P < 0.001), and the basal respiratory rate [(50.03±1.20) pmol/min], maximum respiration rate [(78.07±2.57) pmol/min] and adenosine triphosphate (ATP) production [(25.30±1.21) pmol/min] of MDSCs in the bone marrow of CLP group mice were significantly greater than the basal respiration rate [(34.53±0.96) pmol/min, (t = 17.41, P < 0.001)], maximum respiration rate [(42.57±1.87) pmol/min, (t = 19.33, P < 0.001)], and ATP production [(12.63±0.96) pmol/min, (t = 14.18, P < 0.001)] of sham group. Leucine, threonine, glycine, etc. were potential biomarkers of septic MDSCs (all P < 0.05). The increased amino acids were mainly enriched in metabolic pathways, such as malate-aspartate shuttle, ammonia recovery, alanine metabolism, glutathione metabolism, phenylalanine and tyrosine metabolism, urea cycle, glycine and serine metabolism, β-alanine metabolism, glutamate metabolism, arginine and proline metabolism. Conclusion: The enhanced mitochondrial oxidative phosphorylation, malate-aspartate shuttle and alanine metabolism in MDSCs of CLP mice may provide raw materials for mitochondrial aerobic respiration, thereby promoting the immunosuppressive function of MDSCs. Blocking the above metabolic pathways may reduce the risk of secondary infection in sepsis and improve the prognosis.

Key words: Sepsis, Myeloid-derived suppressor cell, Aerobic respiration, Amino acid metabolomics

CLC Number: 

  • R363.1

Figure 1

Proportion and oxidative respiration of bone marrow MDSCs in CLP and sham mice A, survival curve of CLP group mice; B, representative plot of flow cytometry of mouse bone marrow MDSCs; C, comparison of MDSCs content between sham group and CLP group; D, OCR curves of MDSCs in sham and CLP groups; E, F, G, basal, ATP production and maximum respiration OCR of MDSCs in sham and CLP groups. CLP, cecal ligation and puncture; MDSCs, myeloid-derived suppressor cells; OCR, oxygen consumption rate; FCCP, car-bonyl cyanide-p-trifluoromethoxyphenolhydrazone; ATP, adenosine triphosphate. *P < 0.001."

Figure 2

Composition of various metabolites of MDSCs in CLP and sham groups CLP, cecal ligation and puncture; MDSCs, myeloid-derived suppressor cells. *P < 0.001."

Table 1

One-dimensional analysis of amino acid and oligopeptide contents in MDSCs of mice in sham-operated group and CLP group  /(μmol/L)"

Amino acids Sham group (n=5) CLP group (n=5) t/U value P log2FC
Glycine 386.660±77.645 995.180±65.567 13.390 < 0.001 1.364
Leucine 219.580±34.095 587.560±79.165 9.546 < 0.001 1.420
Aspartic acid 122.680±44.956 555.440±118.618 7.628 0.001 2.179
Lysine 224.020±47.647 666.820±134.086 6.958 0.001 1.574
Histidine 98.200±16.996 202.380±36.155 5.831 0.001 1.043
Asparagine 64.500±28.406 140.580±23.324 4.629 0.002 1.124
Valine 195.400±45.947 548.020±136.323 5.481 0.003 1.488
Threonine 112.160±5.280 269.220±40.306 0.000 0.008 1.322
Serine 444.380±60.045 1 251.500±187.629 0.000 0.008 1.676
Phenylalanine 116.560±11.250 301.400±51.594 0.000 0.008 1.563
Tyrosine 89.080±14.074 243.940±47.185 0.000 0.008 1.393
Glutamate 522.220±186.936 2 490.800 (1 678.900, 2 631.900) 0.000 0.008 2.475
4-hydroxyproline 217.480±54.856 729.100±189.424 0.000 0.008 1.995
Tryptophan 24.700±9.100 103.200±30.850 0.000 0.008 2.405
Alanine 921.900 (870.000, 948.200) 3 029.320±780.214 0.000 0.008 1.801
Proline 96.800 (95.400, 104.800) 375.700±121.282 0.000 0.008 2.085
Taurine 4 646.620±2 425.105 8 336.720±739.823 0.000 0.008 0.472
Citrulline 49.140±18.249 124.040±39.186 3.874 0.009 1.336
Methionine 62.860±20.195 127.240±6.354 0.000 0.012 1.122
5-hydroxylysine 2.516±2.567 15.620±8.233 0.000 0.012 2.204
Aminoadipic acid 14.500 (13.800, 14.900) 42.380±13.225 1.000 0.016 1.814
Glutamine 297.100 (277.400, 300.600) 1 452.940±559.859 1.000 0.016 2.448
α-aminobutyric acid 27.740±14.200 83.200±34.351 3.336 0.019 1.585
Arginine 137.380±68.239 305.500±105.690 2.988 0.021 1.153
Cystine 0.180±0.000 12.376±12.628 2.500 0.025 6.207
Ornithine 91.960±58.453 312.800±160.012 2.899 0.033 1.766
Kynurenine 8.520±1.359 10.340±1.383 2.099 0.069 0.279
Carnosine 20.138±15.920 40.700±24.508 1.573 0.160 1.015
Glutathione 273.980±94.760 189.800 (187.300, 268.800) 7.000 0.310 -0.591

Figure 3

OPLS-DA multidimensional analysis of metabolites in MDSCs of mice in CLP and sham groups CLP, cecal ligation and puncture; MDSCs, myeloid-derived suppressor cells; OPLS-DA, orthogonal partial least square discriminant analysis."

Table 2

Multivariate statistical analysis of amino acid and oligopeptide contents in MDSCs of mice in sham and CLP groups  /(μmol/L)"

Amino acids Sham group (n=5) CLP group (n=5) VIP Corr.Coeffs.
Leucine 219.580±34.095 587.560±79.165 1.144 0.977
Threonine 112.160±5.280 269.220±40.306 1.142 0.976
Glycine 386.660±77.645 995.180±65.567 1.135 0.970
Serine 444.380±60.045 1251.500±187.629 1.129 0.964
Phenylalanine 116.560±11.250 301.400±51.594 1.124 0.960
Tyrosine 89.080±14.074 243.940±47.185 1.121 0.957
Aspartic acid 122.680±44.956 555.440±118.618 1.117 0.954
Glutamate 522.220±186.936 2 490.800 (1 678.900, 2 631.900) 1.107 0.945
Methionine 62.860±20.195 127.240±6.354 1.107 0.946
Lysine 224.020±47.647 666.820±134.086 1.107 0.946
4-hydroxyproline 217.480±54.856 729.100±189.424 1.087 0.928
Histidine 98.200±16.996 202.380±36.155 1.076 0.919
Tryptophan 24.700±9.100 103.200±30.850 1.075 0.918
Valine 195.400±45.947 548.020±136.323 1.074 0.918
Alanine 921.900 (870.000, 948.200) 3 029.320±780.214 1.024 0.874
Proline 96.800 (95.400, 104.800) 375.700±121.282 1.021 0.872
Asparagine 64.500±28.406 140.580±23.324 1.009 0.862
Aminoadipic acid 14.500 (13.800, 14.900) 42.380±13.225 0.997 0.852
Citrulline 49.140±18.249 124.040±39.186 0.982 0.838
Glutamine 297.100 (277.400, 300.600) 1 452.940±559.859 0.967 0.826
Taurine 4 646.620±2 425.105 8 336.720±739.823 0.961 0.821
α-aminobutyric acid 27.740±14.200 83.200±34.351 0.945 0.807
5-hydroxylysine 2.516±2.567 15.620±8.233 0.925 0.790
Ornithine 91.960±58.453 312.800±160.012 0.888 0.758
Arginine 137.380±68.239 305.500±105.690 0.863 0.737
Cystine 0.180±0.000 12.376±12.628 0.775 0.662
Kynurenine 8.520±1.359 10.340±1.383 0.704 0.601
Carnosine 20.138±15.920 40.700±24.508 0.540 0.461
Glutathione 273.980±94.760 189.800 (187.300, 268.800) 0.362 -0.310

Figure 4

Pathway enrichment analysis of marker metabolites in MDSCs of CLP group mice A, heat map of changes in marker metabolite content in MDSCs in the sham group and CLP group; B, bar graphs of enrichment analysis of metabolite pathways for MDSCs markers in sepsis, all P < 0.001. CLP, cecal ligation and puncture; MDSCs, myeloid-derived suppressor cells."

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