TY - JOUR
T1 - Human alveolar macrophages do not rely on glucose metabolism upon activation by lipopolysaccharide
AU - Pereverzeva, Liza
AU - van Linge, Christine C. A.
AU - Schuurman, Alex R.
AU - Klarenbeek, Augustijn M.
AU - Ramirez Moral, Ivan
AU - Otto, Natasja A.
AU - Peters-Sengers, Hessel
AU - Butler, Joe M.
AU - Schomakers, Bauke V.
AU - van Weeghel, Michel
AU - Houtkooper, Riekelt H.
AU - Wiersinga, W. Joost
AU - Bonta, Peter I.
AU - Annema, Jouke T.
AU - de Vos, Alex F.
AU - van der Poll, Tom
N1 - Funding Information: Liza Pereverzeva was supported by Netherlands Organization for Health Research and Development (ZonMW, program JPIAMR, grant 547001008 ). Funding Information: Natasja Otto was supported by ZonMW (grant 40-00812-98-14016 ). Funding Information: Ivan Ramirez-Moral was funded by the Era-Net JPIAMR/ZonMW (grant 50-52900-98-201 ). Funding Information: Christine Linge is supported by European Union Horizon 2020 (FAIR project, grant 847786 ). Publisher Copyright: © 2022 The Authors
PY - 2022/10/1
Y1 - 2022/10/1
N2 - Most macrophages generate energy to mount an inflammatory cytokine response by increased glucose metabolism through intracellular glycolysis. Previous studies have suggested that alveolar macrophages (AMs), which reside in a glucose-poor natural environment, are less capable to utilize glycolysis and instead rely on other substrates to fuel oxidative phosphorylation (OXPHOS) for energy supply. At present, it is not known whether AMs are capable to use glucose metabolism to produce cytokines when other metabolic options are blocked. Here, we studied human AMs retrieved by bronchoalveolar lavage from healthy subjects, and examined their glucose metabolism in response to activation by the gram-negative bacterial component lipopolysaccharide (LPS) ex vivo. The immunological and metabolic responses of AMs were compared to those of cultured blood monocyte-derived macrophages (MDMs) from the same subjects. LPS stimulation enhanced cytokine release by both AMs and MDMs, which was associated with increased lactate release by MDMs (reflecting glycolysis), but not by AMs. In agreement, LPS induced higher mRNA expression of multiple glycolytic regulators in MDMs, but not in AMs. Flux analyses of [13C]-glucose revealed no differences in [13C]-incorporation in glucose metabolism intermediates in AMs. Inhibition of OXPHOS by oligomycin strongly reduced LPS-induced cytokine production by AMs, but not by MDMs. Collectively, these results indicate that human AMs, in contrast to MDMs, do not use glucose metabolism during LPS-induced activation and fully rely on OXPHOS for cytokine production.
AB - Most macrophages generate energy to mount an inflammatory cytokine response by increased glucose metabolism through intracellular glycolysis. Previous studies have suggested that alveolar macrophages (AMs), which reside in a glucose-poor natural environment, are less capable to utilize glycolysis and instead rely on other substrates to fuel oxidative phosphorylation (OXPHOS) for energy supply. At present, it is not known whether AMs are capable to use glucose metabolism to produce cytokines when other metabolic options are blocked. Here, we studied human AMs retrieved by bronchoalveolar lavage from healthy subjects, and examined their glucose metabolism in response to activation by the gram-negative bacterial component lipopolysaccharide (LPS) ex vivo. The immunological and metabolic responses of AMs were compared to those of cultured blood monocyte-derived macrophages (MDMs) from the same subjects. LPS stimulation enhanced cytokine release by both AMs and MDMs, which was associated with increased lactate release by MDMs (reflecting glycolysis), but not by AMs. In agreement, LPS induced higher mRNA expression of multiple glycolytic regulators in MDMs, but not in AMs. Flux analyses of [13C]-glucose revealed no differences in [13C]-incorporation in glucose metabolism intermediates in AMs. Inhibition of OXPHOS by oligomycin strongly reduced LPS-induced cytokine production by AMs, but not by MDMs. Collectively, these results indicate that human AMs, in contrast to MDMs, do not use glucose metabolism during LPS-induced activation and fully rely on OXPHOS for cytokine production.
KW - Alveolar macrophages
KW - Glucose metabolism
KW - Lipopolysaccharide
KW - Monocyte-derived macrophages
UR - http://www.scopus.com/inward/record.url?scp=85134721048&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbadis.2022.166488
DO - https://doi.org/10.1016/j.bbadis.2022.166488
M3 - Article
C2 - 35835414
SN - 0925-4439
VL - 1868
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 10
M1 - 166488
ER -