Metabolic rewiring is important regulatory mechanism of the inflammatory activation of immune cells. In 2013, seminal work by the O'Neill group demonstrated that succinate (TCA cycle metabolite) acts as a key proinflammatory signal in macrophages, and this work was followed by intense studies of succinate's functional roles in macrophages and other contexts. Yet, regulatory mechanisms that control succinate accumulation and utilization still remain unknown. In our recent work, using a systems biology approach, we dissected the global metabolic architecture of macrophage activation, corroborated O'Neill's result and showed that upon LPS stimulation, the TCA cycle becomes disrupted by inactivating isocitrate dehydrogenase (Idh1). This TCA cycle breakpoint frees citrate to participate in the production of acetyl-CoA, an important fatty acid synthesis precursor, and in the intracellular production of itaconic acid, a dicarboxilyc acid metabolite structurally very similar to succinate. Our preliminary data suggest that high production of itaconate during macrophage activation is functionally critical, as it provides a natural metabolic regulator to balance the pro-inflammatory function of succinate. Indeed, by pre-treating macrophages in vitro with itaconate, we observed significant reduction in the production of NO, IL-6, IL-1? in response to LPS stimulation, as well as dose-dependent inhibition of IL-1? and IL-18 production during inflammasome activation. We find that itaconate, like other structural mimetics of succinate (e.g. malonate) is serving as inhibitor of succinate dehydrogenase (Sdh), an enzyme also known as complex II in the electron transfer chain (ETC) affecting both ROS production and activity of TCA cycle both in vitro and in vivo. In this grant, we plan to decipher the regulatory role of itaconate and determine its functional impact on immune responses in vivo.
Metabolic rewiring is important regulatory mechanism controlling activation of the immune cells. Succinate is one of the major metabolic regulators of macrophage activation, playing distinct proinflammatory role. Our preliminary data suggest that high production of itaconate during macrophage activation is functionally critical, as it provides a natural, structural mimetic metabolic regulator to balance the pro-inflammatory function of succinate. In this grant, we plan to decipher the regulatory role of itaconate and determine its functional impact on immune responses in vivo using newly generated Irg1-/- and Irg1fl/fl mice that lack itaconate producing enzyme.
| Nair, Sharmila; Huynh, Jeremy P; Lampropoulou, Vicky et al. (2018) Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection. J Exp Med 215:1035-1045 |
| Bambouskova, Monika; Gorvel, Laurent; Lampropoulou, Vicky et al. (2018) Electrophilic properties of itaconate and derivatives regulate the I?B?-ATF3 inflammatory axis. Nature 556:501-504 |
