The inflammasome is a protein complex that comprises an intracellular sensor (typically a Nod-like receptor), the precursor procaspase-1 and the adaptor ASC. Inflammasome activation leads to the ...maturation of caspase-1 and the processing of its substrates, interleukin 1β (IL-1β) and IL-18. Although initially the inflammasome was described as a complex that affects infection and inflammation, subsequent evidence has suggested that inflammasome activation influences many metabolic disorders, including atherosclerosis, type 2 diabetes, gout and obesity. Another feature of inflammation in general and the inflammasome specifically is that the activation process has a profound effect on aerobic glycolysis (the 'Warburg effect'). Here we explore how the Warburg effect might be linked to inflammation and inflammasome activation.
A recent focus meeting on Controlling Acute Inflammation was held in London, April 27-28, 2006, organized by D.W. Gilroy and S.D. Brain for the British Pharmacology Society. We concluded at the ...meeting that a consensus report was needed that addresses the rapid progress in this emerging field and details how the specific study of resolution of acute inflammation provides leads for novel anti-inflammatory therapeutics, as well as defines the terms and key components of interest in the resolution process within tissues as appreciated today. The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. It is now evident that endogenous biochemical pathways activated during defense reactions can counter-regulate inflammation and promote resolution. Hence, resolution is an active rather than a passive process, as once believed, which now promises novel approaches for the treatment of inflammation-associated diseases based on endogenous agonists of resolution.--Serhan, C. N., Brain, S. D., Buckley, C. D., Gilroy, D. W., Haslett, C., O'Neill, L. A. J., Perretti, M., Rossi, A. G., Wallace, J. L. Resolution of inflammation: state of the art, definitions and terms.
Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular ...coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
Bacterial lipopolysaccharide (LPS) stimulation of macrophages and inflammation via the Toll-like receptor 4 (TLR4) signaling pathway through NF-κΒ generates reactive oxygen species (ROS) and ...proinflammatory cytokines such as IL-1β, IL-6, and TNFα. Because glutathione transferase Omega 1-1 (GSTO1-1) can catalyze redox reactions such as the deglutathionylation of proteins and has also been implicated in the release of IL-1β we investigated its role in the development of LPS-mediated inflammation. Our data show that shRNA knockdown of GSTO1-1 in macrophage-like J774.1A cells blocks the expression of NADPH oxidase 1 and the generation of ROS after LPS stimulation. Similar results were obtained with a GSTO1-1 inhibitor. To maintain high ROS levels during an inflammatory response, LPS stimulation causes the suppression of enzymes such as catalase and glutathione peroxidase that protect against oxidative stress. The knockdown of GSTO1-1 also attenuates this response. Our data indicate that GSTO1-1 needs to be catalytically active and mediates its effects on the LPS/TLR4 inflammatory pathway upstream of NF-κΒ. These data suggest that GSTO1-1 is a novel target for anti-inflammatory intervention.
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•GSTO1-1 regulates LPS-stimulated reactive oxygen species generation via TLR4.•GSTO1-1 decreases global protein glutathionylation levels in J774.1A macrophages.•NF-κB nuclear translocation is blocked in GSTO1-1-deficient J774.1A cells.
Atherosclerosis is the cause of morbiditiy for 70% of patients with type 2 diabetes. In both of these diseases, a protein complex known as the inflammasome is stimulated to activate interleukin-1β ...(IL-1β) and IL-18, which are pathogenic inflammatory cytokines. Triggers for the inflammasome are obesity-related factors, such as cholesterol crystals in atherosclerosis, or hyperglycemia, ceramides, and islet amyloid polypeptide in type 2 diabetes. Therapeutics that target IL-1β in clinical trials for type 2 diabetes might also decrease the incidence of atherosclerosis.
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.
Summary
An understanding of lipopolysaccharide (LPS) signal transduction is a key goal in the effort to provide a molecular basis for the lethal effect of LPS during septic shock and point the way to ...novel therapies. Rapid progress in this field during the last 6 years has resulted in the discovery of not only the receptor for LPS – Toll‐like receptor 4 (TLR4) – but also in a better appreciation of the complexity of the signalling pathways activated by LPS. Soon after the discovery of TLR4, the formation of a receptor complex in response to LPS, consisting of dimerized TLR4 and MD‐2, was described. Intracellular events following the formation of this receptor complex depend on different sets of adapters. An early response, which is dependent on MyD88 and MyD88‐like adapter (Mal), leads to the activation of nuclear factor‐κB (NF‐κB). A later response to LPS makes use of TIR‐domain‐containing adapter‐inducing interferon‐β (TRIF) and TRIF‐related adapter molecule (TRAM), and leads to the late activation of NF‐κB and IRF3, and to the induction of cytokines, chemokines, and other transcription factors. As LPS signal transduction is an area of intense research and rapid progress, this review is intended to sum up our present understanding of the events following LPS binding to TLR4, and we also attempt to create a model of the signalling pathways activated by LPS.
Targeting Toll-like receptors: emerging therapeutics? O'Neill, Luke A. J; Hennessy, Elizabeth J; Parker, Andrew E
Nature reviews. Drug discover/Nature reviews. Drug discovery,
04/2010, Letnik:
9, Številka:
4
Journal Article
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There is a growing interest in the targeting of Toll-like receptors (TLRs) for the prevention and treatment of cancer, rheumatoid arthritis, inflammatory bowel disease and systemic lupus ...erythematosus (SLE). Several new compounds are now undergoing preclinical and clinical evaluation, with a particular focus on TLR7 and TLR9 activators as adjuvants in infection and cancer, and inhibitors of TLR2, TLR4, TLR7 and TLR9 for the treatment of sepsis and inflammatory diseases. Here, we focus on TLRs that hold the most promise for drug discovery research, highlighting agents that are in the discovery phase and in clinical trials,and on the emerging new aspects of TLR-mediated signalling - such as control by ubiquitination and regulation by microRNAs - that might offer further possibilities of therapeutic manipulation.
A repertoire of 10 TLRs mediate the first response to all microbes that infect mammals. They are the long sought receptors for a wide range of microbial products. Notable examples include TLR4 which ...recognizes LPS from gram negative bacteria, TLR3 which recognizes viral double-stranded RNA and TLR9 which recognizes CpG DNA motifs, found commonly in both viruses and bacteria. TLRs are increasingly being implicated in both infectious and inflammatory diseases, notable examples being sepsis, inflammatory bowel disease, atherosclerosis and asthma. There is therefore great interest in targeting TLRs therapeutically since blocking TLRs will result in a decrease in the production of inflammatory mediators such as TNF. This volume covers our current understanding of TLRs, and their role in inflammation. Given the primacy of TLRs in the inflammatory process and their emerging role in inflammatory diseases the book is of great interest to researchers working in inflammation and immunology.
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