TY - JOUR
T1 - Intracellular pyruvate levels positively correlate with cytokine production capacity in tolerant monocytes from patients with pneumonia
AU - Otto, Natasja A.
AU - Butler, Joe M.
AU - Schuurman, Alex R.
AU - Brands, Xanthe
AU - Haak, Bastiaan W.
AU - Klarenbeek, Augustijn M.
AU - van Weeghel, Michel
AU - Houtkooper, Riekelt H.
AU - Jakobs, Marja E.
AU - Faber, Daniël R.
AU - de Vos, Alex F.
AU - Wiersinga, W. Joost
AU - Scicluna, Brendon P.
AU - van der Poll, Tom
N1 - Funding Information: The authors would like to thank all the subjects who participated in this study. We thank Linda Koster from the Core Facility Genomics, Amsterdam UMC for the technical assistance regarding the preparations for the RNA sequencing analysis. We thank Barbara S. Dierdorp and Tamara Dekker for their help with the workup of the cytokine measurements. This work was supported by ZonMW (grants 40-00812-98-14016, 50-53000-98-139 and 522008011) and European Commission (Horizon 2020, ImmunoSep, grant number 847422). Funding Information: Natasja A. Otto reports financial support was provided by Netherlands Organisation for Health Research and Development. Funding Information: This work was supported by ZonMW (grants 40-00812-98-14016 , 50-53000-98-139 and 522008011 ) and European Commission ( Horizon 2020 , ImmunoSep, grant number 847422 ). Publisher Copyright: © 2022 The Authors
PY - 2022/11/1
Y1 - 2022/11/1
N2 - Background: Community-acquired pneumonia (CAP) is responsible for a high morbidity and mortality worldwide. Monocytes are essential for pathogen recognition and the initiation of an innate immune response. Immune cells induce intracellular glycolysis upon activation to support several functions. Objective: To obtain insight in the metabolic profile of blood monocytes during CAP, with a focus on glycolysis and branching metabolic pathways, and to determine a possible association between intracellular metabolite levels and monocyte function. Methods: Monocytes were isolated from blood of patients with CAP within 24 h of hospital admission and from control subjects matched for age, sex and chronic comorbidities. Changes in glycolysis, oxidative phosphorylation (OXPHOS), tricarboxylic acid (TCA) cycle and the pentose phosphate pathway were investigated through RNA sequencing and metabolomics measurements. Monocytes were stimulated ex vivo with lipopolysaccharide (LPS) to determine their capacity to produce tumor necrosis factor (TNF), interleukin (IL)-1β and IL-10. Results: 50 patients with CAP and 25 non-infectious control subjects were studied. When compared with control monocytes, monocytes from patients showed upregulation of many genes involved in glycolysis, including PKM, the gene encoding pyruvate kinase, the rate limiting enzyme for pyruvate production. Gene set enrichment analysis of OXPHOS, the TCA cycle and the pentose phosphate pathway did not reveal differences between monocytes from patients and controls. Patients' monocytes had elevated intracellular levels of pyruvate and the TCA cycle intermediate α-ketoglutarate. Monocytes from patients were less capable of producing cytokines upon LPS stimulation. Intracellular pyruvate (but not α-ketoglutarate) concentrations positively correlated with IL-1β and IL-10 levels released by patients' (but not control) monocytes upon exposure to LPS. Conclusion: These results suggest that elevated intracellular pyruvate levels may partially maintain cytokine production capacity of hyporesponsive monocytes from patients with CAP.
AB - Background: Community-acquired pneumonia (CAP) is responsible for a high morbidity and mortality worldwide. Monocytes are essential for pathogen recognition and the initiation of an innate immune response. Immune cells induce intracellular glycolysis upon activation to support several functions. Objective: To obtain insight in the metabolic profile of blood monocytes during CAP, with a focus on glycolysis and branching metabolic pathways, and to determine a possible association between intracellular metabolite levels and monocyte function. Methods: Monocytes were isolated from blood of patients with CAP within 24 h of hospital admission and from control subjects matched for age, sex and chronic comorbidities. Changes in glycolysis, oxidative phosphorylation (OXPHOS), tricarboxylic acid (TCA) cycle and the pentose phosphate pathway were investigated through RNA sequencing and metabolomics measurements. Monocytes were stimulated ex vivo with lipopolysaccharide (LPS) to determine their capacity to produce tumor necrosis factor (TNF), interleukin (IL)-1β and IL-10. Results: 50 patients with CAP and 25 non-infectious control subjects were studied. When compared with control monocytes, monocytes from patients showed upregulation of many genes involved in glycolysis, including PKM, the gene encoding pyruvate kinase, the rate limiting enzyme for pyruvate production. Gene set enrichment analysis of OXPHOS, the TCA cycle and the pentose phosphate pathway did not reveal differences between monocytes from patients and controls. Patients' monocytes had elevated intracellular levels of pyruvate and the TCA cycle intermediate α-ketoglutarate. Monocytes from patients were less capable of producing cytokines upon LPS stimulation. Intracellular pyruvate (but not α-ketoglutarate) concentrations positively correlated with IL-1β and IL-10 levels released by patients' (but not control) monocytes upon exposure to LPS. Conclusion: These results suggest that elevated intracellular pyruvate levels may partially maintain cytokine production capacity of hyporesponsive monocytes from patients with CAP.
KW - Community-acquired pneumonia (CAP)
KW - Cytokine production
KW - Monocytes
KW - Pyruvate
KW - Tolerance
UR - http://www.scopus.com/inward/record.url?scp=85136259563&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbadis.2022.166519
DO - https://doi.org/10.1016/j.bbadis.2022.166519
M3 - Article
C2 - 35964875
SN - 0925-4439
VL - 1868
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 11
M1 - 166519
ER -