Translating glycolytic metabolism to innate immunity in dendritic cells

Abstract

Growing evidence supports a role for glycolysis in immune activation. Everts et al. (2014) now show that TLR-mediated stimulation of dendritic cells rapidly induces glycolysis, which regenerates NADPH and TCA intermediates to support fatty acid production. This enhances ER and Golgi membrane synthesis and innate activation of dendritic cells.

Figure 1

TLR-mediated reprogramming of cellular metabolism is a requirement for DC effector functions. TLR signaling via the kinases Tbk1-IKKε and Aktrapidly increases glycolysis by promoting juxtaposition of the rate-limiting glycolytic enzyme HK-II to the outer mitochondrial membrane. Upon translocation,HK-II gains direct access to high concentrations of ATP, which enhances its enzymatic activity. Increased glycolytic flux: a) recharges NADPH through the PPP; b) promotes utilization of citrate and isocitrate for lipogenesis. Together, increased fatty acid synthesis induces ER and Golgi expansion, accommodating cellular demand for the translation, transport and secretion of early activation markers and pro-inflammatory cytokines TNFa and IL-6.