Περίληψη:
Epigenetic reprogramming of myeloid cells, also known as trained
immunity, confers nonspecific protection from secondary infections.
Using histone modification profiles of human monocytes trained with the
Candida albicans cell wall constituent beta-glucan, together with a
genome-wide transcriptome, we identified the induced expression of genes
involved in glucose metabolism. Trained monocytes display high glucose
consumption, high lactate production, and a high ratio of nicotinamide
adenine dinucleotide (NAD+) to its reduced form (NADH), reflecting a
shift in metabolism with an increase in glycolysis dependent on the
activation of mammalian target of rapamycin (mTOR) through a
dectin-1-Akt-HIF-1 alpha (hypoxia-inducible factor-1 alpha) pathway.
Inhibition of Akt, mTOR, or HIF-1 alpha blocked monocyte induction of
trained immunity, whereas the adenosine monophosphate-activated protein
kinase activator metformin inhibited the innate immune response to
fungal infection. Mice with a myeloid cell-specific defect in HIF-1
alpha were unable to mount trained immunity against bacterial sepsis.
Our results indicate that induction of aerobic glycolysis through an
Akt-mTOR-HIF-1 alpha pathway represents the metabolic basis of trained
immunity.
Συγγραφείς:
Cheng, Shih-Chin
Quintin, Jessica
Cramer, Robert A. and
Shepardson, Kelly M.
Saeed, Sadia
Kumar, Vinod and
Giamarellos-Bourboulis, Evangelos J.
Martens, Joost H. A.
Rao,
Nagesha Appukudige
Aghajanirefah, Ali
Manjeri, Ganesh R.
Li,
Yang
Ifrim, Daniela C.
Arts, Rob J. W.
van der Meer, Brian
M. J. W.
Deen, Peter M. T.
Logie, Colin
O'Neill, Luke A. and
Willems, Peter
van de Veerdonk, Frank L.
van der Meer, Jos W. M.
and Ng, Aylwin
Joosten, Leo A. B.
Wijmenga, Cisca and
Stunnenberg, Hendrik G.
Xavier, Ramnik J.
Netea, Mihai G.
