The Toll/IL‐1 receptor (TIR) domain plays a central role in Toll‐like receptor (TLR) signalling. All TLRs contain a cytoplasmic TIR domain, which, upon activation, acts as a scaffold to recruit adaptor proteins. The adaptor proteins MyD88, Mal, TRIF, TRAM and SARM are also characterized by the presence of a TIR domain. MyD88, Mal, TRIF and TRAM associate with the TLRs via homophilic TIR domain interactions whereas SARM utilizes its TIR domain to negatively regulate TRIF. It is well established that the differential recruitment of adaptors to TLRs provides a significant amount of specificity to the TLR‐signalling pathways. Despite this, the TIR–TIR interface has not been well defined. However, structural studies have indicated the importance of TIR domain surfaces in mediating specific TIR–TIR interactions. Furthermore, recent findings regarding the regulation of adaptors provide further insight into the crucial role of the TIR domain in TLR signalling.
The inhibitory effect of pertussis toxin on the action of IL-1 has been investigated. The toxin inhibited IL-1-induced production of IL-2 mRNA and protein in EL4 cells. The B oligomer of the toxin, which was shown to be devoid of ADP-ribosylating activity, proved as inhibitory as the holotoxin. The inhibition was therefore attributable to the binding subunit of the toxin and not to its ability to ADP-ribosylate G proteins. The toxin did not affect the IL-1R binding to its ligand, nor did it inhibit an early post-receptor event, the induction of the transcription factor NF kappa B. This implied that the toxin was not uncoupling IL-1R signaling. The toxin, or its B oligomer, inhibited PGE2 synthesis in human gingival fibroblasts stimulated by IL-1, but not by PMA. Assay of PG synthetic activity in the cells after addition of exogenous arachidonic acid suggested impairment by the toxin of induction of PG-synthesizing enzymes. IL-1 stimulation of IL-6 or collagenase production by fibroblasts was unaffected by pertussis toxin. The binding subunit of the toxin inhibits certain IL-1 responses by virtue of previously unrecognized actions on lymphoid and fibroblastic cells. It does not appear to block early signaling and the inhibition highly unlikely to involve inactivation of a G protein.
No abstract is provided for this article.
Using microarray technologies, it is now possible to analyze the expression of thousands of genes during the activation of immune cells. A recent report by Paola Ricciardi-Castagnoli and co-workers at the University of Milano-Bicocca, Italy demonstrates the usefulness of this approach when addressing how dendritic cells (DCs) respond to live Gram-negative bacteria. Using the D1 DC line (which shows similar maturation in culture to that observed for fresh bone-marrow-derived DCs), they have shown that expression of ≈3000 genes is induced upon incubation with live E. coli. These genes include those involved in cytoskeletal rearrangements, antigen processing, control of migration and apoptosis, and inflammatory responses. Most interestingly, expression of IL-2 was found to be induced rapidly. This did not occur in macrophages and the authors conclude that DCs are involved uniquely in T-cell priming. The usefulness of analysis of global gene expression for immunologists continues to become apparent. Nat. Immunol. (2001) 2, 882–888 LON
. showcase that interferons (IFNs) trigger a functional reprogramming of tumor-associated macrophages (TAMs) by downregulating NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4), a key subunit of mitochondrial complex Ⅳ. This drives a transition from protumor TAMs to antitumor IFN-associated TAMs (IFN-TAMs) through activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This mechanism can be leveraged to boost antitumor immunity and improve responses to immune checkpoint blockade.
No abstract is provided for this article.
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.
Neutrophils are front line cells in immunity that quickly recognize and eliminate pathogens, relying mainly on glycolysis to exert their killing functions. Even though investigations into the influence of metabolic pathways in neutrophil function started in the 1930s, the knowledge of how neutrophils metabolically adapt during a bacterial infection remains poorly understood. In this review, we discuss the current knowledge about the metabolic regulation underlying neutrophils response to bacterial infection. Glycogen metabolism has been shown to be important for multiple neutrophil functions. The potential contribution of metabolic pathways other than glycolysis, such as mitochondrial metabolism, for neutrophil function has recently been explored, including fatty acid oxidation in neutrophil differentiation. Complex III in the mitochondria might also control glycolysis via glycerol-3-phosphate oxidation. Future studies should yield new insights into the role of metabolic change in the anti-bacterial response in neutrophils.
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.
Macrophages play diverse roles including but not limited to homeostatic clearance, detection of invading pathogens and induction of the adaptive immune response. Since their discovery, it has become clear that Toll-like receptors (TLRs) can play a major role in these macrophage functions. This review will describe the TLRs, their signalling pathways and their role in macrophage function.
A growing number of findings highlight the crucial role of metabolic reprogramming in macrophage activation. Metabolic pathways are closely interconnected and recent literature demonstrates the need for glucose metabolism in anti-inflammatory as well as inflammatory macrophages. Moreover, fatty acid oxidation (FAO) not only supports anti-inflammatory responses as described formerly but also drives inflammasome activation in inflammatory macrophages. Hence, defining glycolysis as proinflammatory and FAO as anti-inflammatory may be an oversimplification. Here we review how the rapid growth of the immunometabolism field has improved our understanding of macrophage activation and at the same time has led to an increase in the appearance of contradictory observations. To conclude we discuss current challenges in immunometabolism and present crucial areas for future research.
