Two for the price of one: itaconate and its derivatives as an anti-infective and anti-inflammatory immunometabolite.

The metabolite itaconate (ITA) and its derivatives, both chemically synthesized and endogenous, have emerged as immunoregulators, with roles in limiting inflammation but also having effects on bacterial and viral infection. Some members of the ITA family have been shown to target and inhibit multiple processes in macrophages with recently identified targets, including NLRP3, JAK1, ten-eleven translocation-2 dioxygenases, and TFEB, a key transcription factor for lysosomal biogenesis. They have also been shown to target multiple bacteria, inhibiting their replication, as well as having antiviral effects against viruses such as SARS-CoV2, Zika virus, and Influenza virus. The importance of ITA is highlighted by the fact that several pathogens have developed mechanisms to evade ITA and can manipulate ITA for their own gain. Two newly discovered isomers of ITA, mesaconate and citraconate, are also discussed, which also have immunomodulatory effects. ITA continues to be a fascination, both in terms of inflammation but also as an antibacterial and antiviral agent, with therapeutic potential in immune and inflammatory diseases.

The role of itaconate in host defense and inflammation.

Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is itaconate, which is derived from cis-aconitate by the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on itaconate's emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome. Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and inflammation.

TCA cycle signalling and the evolution of eukaryotes.

A major question remaining in the field of evolutionary biology is how prokaryotic organisms made the leap to complex eukaryotic life. The prevailing theory depicts the origin of eukaryotic cell complexity as emerging from the symbiosis between an α-proteobacterium, the ancestor of present-day mitochondria, and an archaeal host (endosymbiont theory). A primary contribution of mitochondria to eukaryogenesis has been attributed to the mitochondrial genome, which enabled the successful internalisation of bioenergetic membranes and facilitated remarkable genome expansion. It has also been postulated that a key contribution of the archaeal host during eukaryogenesis was in providing 'archaeal histones' that would enable compaction and regulation of an expanded genome. Yet, how the communication between the host and the symbiont evolved is unclear. Here, we propose an evolutionary concept in which mitochondrial TCA cycle signalling was also a crucial player during eukaryogenesis enabling the dynamic control of an expanded genome via regulation of DNA and histone modifications. Furthermore, we discuss how TCA cycle remodelling is a common evolutionary strategy invoked by eukaryotic organisms to coordinate stress responses and gene expression programmes, with a particular focus on the TCA cycle-derived metabolite itaconate.

Bridging the gap - a new role for STAT3 in TLR4-mediated metabolic reprogramming.

Balic et al. describe a new role for STAT3 in TLR4 signalling in macrophages, linking LPS mediated activation of this innate immune receptor to phosphorylation of mitochondrial STAT3, resulting in distinct metabolic reprogramming.

GOTcha: lncRNA-ACOD1 targets metabolism during viral infection.

Long-noncoding RNAs (lncRNAs) are emerging as important regulators of cellular processes, but few have been functionally characterized in host-pathogen interactions. A recent report in Science demonstrates a mechanistic role for a novel lncRNA in directly binding an essential metabolic enzyme, glutamic-oxaloacetic transaminase (GOT2); this interaction benefits viral replication via alteration of host metabolism.