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Deregulation of Toll-like receptor (TLR) mediated responses can have devastating effects on the host if left unchecked. It is, therefore, critical that control is exerted at several levels. In this review, we discuss post-translational modification of TLRs and their associated signaling molecules as one such means of control. In particular, we focus on the phosphorylation, ubiquitination and de-ubiquitination of various components of TLR signaling pathways.
Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.
The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.
The Krebs cycle is an amphibolic pathway operating in the mitochondrial matrix of all eukaryotic organisms. In response to proinflammatory stimuli, macrophages and dendritic cells undergo profound metabolic remodelling to support the biosynthetic and bioenergetic requirements of the cell. Recently, it has been discovered that this metabolic shift also involves the rewiring of the Krebs cycle to regulate cellular metabolic flux and the accumulation of Krebs cycle intermediates, notably, citrate, succinate and fumarate. Interestingly, a new role for Krebs cycle intermediates as signalling molecules and immunomodulators that dictate the inflammatory response has begun to emerge. This review will discuss the latest developments in Krebs cycle rewiring and immune cell effector functions, with a particular focus on the regulation of cytokine production.
No abstract is provided for this article.
Conference Abstract| October 01 2001 Antithrombin III and hirudin inhibits LPS-mediated NF-κB activation A. Mansell; A. Mansell 1Department of Biochemistry, Trinity College Dublin Search for other works by this author on: This Site PubMed Google Scholar L.A.J. O'Neill L.A.J. O'Neill 1Department of Biochemistry, Trinity College Dublin Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (2001) 29 (5): A127. https://doi.org/10.1042/bst029a127 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation A. Mansell, L.A.J. O'Neill; Antithrombin III and hirudin inhibits LPS-mediated NF-κB activation. Biochem Soc Trans 1 October 2001; 29 (5): A127. doi: https://doi.org/10.1042/bst029a127 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 2001 Biochemical Society2001 Article PDF first page preview Close Modal You do not currently have access to this content.
Signal transduction processes activated by Toll-like receptors (TLRs) include the important transcription factor NF-κB and 2 MAP kinases, p38 and Jun N-terminal kinase. These signals ultimately give rise to increased expression of a multitude of pro-inflammatory proteins. Receptor-proximal proteins involved in signalling by all TLRs include the adapter MyD88, 3 IRAKs (IRAK-4, IRAK and IRAK-2), Tollip, Traf-6 and TAK-1. Differences between signals generated by TLRs are emerging, with both TLR4 and TLR2 signalling requiring an additional adapter termed MyD88-adapter-like (Mal; also known as TIRAP). MyD88 and Mal both have a homologous Toll/IL-1 receptor (TIR) domain although they differ in their N-termini, with MyD88 possessing a death domain. In addition, structural models reveal marked differences in surface charges which, when taken with surface charge differences between TLR2 and TLR4 TIR domains, may indicate that TLR4 but not TLR2 recruits Mal directly. Another difference is that Mal can become phosphorylated. Future studies on Mal will reveal specificities in signal transduction by different TLRs, which may ultimately provide molecular explanations for specificities in the innate immune response to infection.
The mucosal surfaces of the gastrointestinal tract are continually exposed to an enormous antigenic load of microbial and dietary origin, yet homeostasis is maintained. Pattern recognition molecules (PRMs) have a key role in maintaining the integrity of the epithelial barrier and in promoting maturation of the mucosal immune system. Commensal bacteria modulate the expression of a broad range of genes involved in maintaining epithelial integrity, inflammatory responses, and production of antimicrobial peptides. Mice deficient in PRMs can develop intestinal inflammation, which is dependent on the microbiota, and in humans, PRM polymorphisms are associated with exacerbated inflammatory bowel disease. Innate immune responses and epithelial barrier function are regulated by PRM-induced signaling at multiple levels, from the selective expression of receptors on mucosal cells or compartments to the expression of negative regulators. Here, we describe recent advances in our understanding of innate signaling pathways, particularly by Toll-like receptors and nucleotide-binding domain and leucine-rich repeat containing receptors at mucosal surfaces.
No abstract is provided for this article.
Metabolites have functions in the immune system independent of their conventional roles as sources or intermediates in biosynthesis and bioenergetics. We are still in the pioneering phase of gathering information about the functions of specific metabolites in immunoregulation. In this review, we cover succinate, itaconate, α-ketoglutarate, and lactate as examples. Each of these metabolites has a different story of how their immunoregulatory functions were discovered and how their roles in the complex process of inflammation were revealed. Parallels and interactions are emerging between metabolites and cytokines, well-known immunoregulators. We depict molecular mechanisms by which metabolites prime cellular and often physiological changes focusing on intra- and extra-cellular activities and signaling pathways. Possible therapeutic opportunities for immune and inflammatory diseases are emerging.
In times when only single-cell organisms populated the earth, some evolved to use energy from oxygen. Then, one of these aerobic bacteria formed an endosymbiotic alliance with larger anaerobic bacteria. The smaller cell continued to use oxygen as a source of energy but continued to do so from the safety of a new home. As a means to pay rent, it started to share its energy with the host. In evolutionary terms, this deal offered the platform to dominate other forms of simple organisms, eventually forming eukaryotic cells as we know them today. The small ingested cell became the mitochondrion, increasing mutual dependence with the bigger cell, but retaining its main task of harnessing energy from oxygen consumption. This helped to build other specialized organelles within the bigger cell in time leading to multicellular organisms, including human beings. This deal made a long time ago determined the world as we know it and is responsible for all of the diversity around us. In this book, while we will not cover topics as broad as the foundation and evolution of our species, we will focus specifically on how regulation of cellular energy affects immune cell functions, enabling host defense during infection or injury. Employing multiple examples, we will illustrate how studying cellular energy of the immune system can be exploited to fight diseases.
The electron transport chain (ETC) couples electron transfer with proton pumping to generate ATP and it also regulates particular innate and adaptive immune cell function. While NLRP3 inflammasome activation was initially linked to reactive oxygen species (ROS) produced from Complexes I and III, recent research suggests that an intact ETC fueling ATP is needed. Complex II may be responsible for Th1 cell proliferation and in some cases, effector cytokine production. Complex III is required for regulatory T (Treg) cell function, while oxidative phosphorylation (OXPHOS) and Complexes I, IV, and V sustain proliferation and antibody production in B lymphocytes, with OXPHOS also being required for B regulatory (Breg) cell function. Despite challenges, the ETC shows therapeutic targeting potential for immune-related diseases and in immuno-oncology.
