Activation of macrophages and dendritic cells （DCs） by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation （OXPHOS）, similar ...to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-la （HIF-la） plays an important role un- der conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid （TCA） cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-la and pro- motes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity.
Macrophages undergo metabolic rewiring during polarization but details of this process are unclear. In this issue of Immunity, Jha et al. (2015) report a systems approach for unbiased analysis of ...cellular metabolism that reveals key metabolites and metabolic pathways required for distinct macrophage polarization states.
Macrophages undergo metabolic rewiring during polarization but details of this process are unclear. Jha et al. report a systems approach for unbiased analysis of cellular metabolism that reveals key metabolites and metabolic pathways required for distinct macrophage polarization states.
Signal transduction pathways activated by Toll-like receptors (TLRs) have continued to be a major focus of research for investigators interested in the initiation of innate immune responses and the ...induction of pro-inflammatory cytokines and type I interferons during infection. Biochemical details of the major signalling pathways have now been obtained, and the specific signalling pathways activated by different TLRs are being elucidated. New insights into the activation of IRF family members, notably IRF3, IRF5 and IRF7, have been obtained, and interesting spatiotemporal aspects of signalling by MyD88 leading to IRF7 activation revealed. Adapters in TLR signalling are targets for inhibition, both by endogenous regulators and by virally derived proteins. Selective targeting of pathways by anti-inflammatory glucocorticoids also indicates the potential for modulating TLR signalling therapeutically.
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.
Highlights ► Overview of the control of NLRP3 activity by the cellular redox environment. ► miRNA-223 and viral factors can inhibit NLRP3. ► Kinase and calcium signalling are emerging as regulators ...of NLRP3 activation. ► Outline of recent findings on ubiquitination and the mechanism of NLRP3 priming. ► Discussion of pharmacological manipulation of NLRP3 inflammasome activity.
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.
In recent years the importance of the localisation and trafficking of Toll-like receptors (TLRs) and their adaptors within the cell has become apparent. Localisation and trafficking of both cell ...surface and endosomal TLRs, alongside their adaptors, appears to play an important role not only in ligand recognition but also in the downregulation of signaling following ligand stimulation. Chaperones, such as gp96, PRAT4A and Unc93B1 play a role in TLR localisation. TLR4 cycles between the Golgi and the plasma membrane until engaged by LPS. The MyD88-dependent pathway is then initiated at the plasma membrane, followed by the movement of the TLR4 complex into the endosome where the MyD88-independent pathway is activated. Several proteins, including Triad3A and TAG appear to be involved in the movement of TLR4 to the lysosome for degradation.
Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the 'classically activated' M1 macrophage enhances pro-inflammatory and microbicidal ...responses, important for eradicating bacteria such as
. By contrast, 'alternatively activated' M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here, we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.
Highlights ► TLRs have been implicated in the pathogenesis of many inflammatory diseases and cancer. ► TLRs are being targeted by agonists or antagonists to control key processes in innate immunity. ...► These TLR targeted therapeutics have clinical applications in a wide range of conditions. ► Many are undergoing evaluation in clinical trials.
In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their ...function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
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