The cGAS-STING signalling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage. Underlying this broad involvement of the cGAS-STING ...pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules. Insights into the structural and molecular biology of the cGAS-STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS-STING axis in a number of inflammatory diseases in humans. Here, we outline the principal elements of the cGAS-STING signalling cascade and discuss the general mechanisms underlying the association of cGAS-STING activity with various autoinflammatory, autoimmune and degenerative diseases. Finally, we outline the chemical nature of recently developed cGAS and STING antagonists and summarize their potential clinical applications.
Inflammation is a condition which contributes to a range of human diseases. It involves a multitude of cell types, chemical mediators, and interactions. Eicosapentaenoic acid (EPA) and ...docosahexaenoic acid (DHA) are omega-3 (n−3) fatty acids found in oily fish and fish oil supplements. These fatty acids are able to partly inhibit a number of aspects of inflammation including leukocyte chemotaxis, adhesion molecule expression and leukocyte–endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n−6 fatty acid arachidonic acid, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of marine n−3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor peroxisome proliferator activated receptor γ and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked, although the full extent of this is not yet elucidated. Animal experiments demonstrate benefit from marine n−3 fatty acids in models of rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in RA demonstrate benefit, but clinical trials of fish oil in IBD and asthma are inconsistent with no overall clear evidence of efficacy. This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: analysis and biological relevance”.
•Inflammation is a condition which contributes to a range of human diseases.•Marine n−3 fatty acids partly inhibit a number of aspects of inflammation.•Several mechanisms explain the anti-inflammatory actions of marine n−3 fatty acids.•Animal experiments demonstrate benefits of marine n−3 fatty acids.•Trials of marine n−3 fish oil in patients are generally inconsistent.
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Macrophages are central to the pathophysiology of rheumatoid arthritis (RA). They constitute the main source of pro-inflammatory cytokines and chemokines such as TNF and IL-1β, they ...activate a wide range of immune and non-immune cells, and they secrete diverse tissue degrading enzymes driving chronic pro-inflammatory, tissue destructive and pain responses in RA. However, they can also produce anti-inflammatory cytokines such as IL-10, secrete inhibitors of tissue degrading enzymes and promote immunoregulatory and protective responses, suggesting the existence of macrophages with distinct and diverse functional activities. Although the underlying basis of this phenomenon has remained obscure for years, emerging evidence has now provided insight into the mechanisms and molecular processes involved. Here, we review current knowledge on the biology of macrophages in RA, and highlight recent literature on the heterogeneity, origins and ontogeny of macrophages as part of the mononuclear phagocyte system. We also discuss their plasticity in the context of the M1/M2 paradigm, and the emerging theme of metabolic rewiring as a major mechanism for programming macrophage functions and pro-inflammatory activities. This sheds light into the many facets of macrophages in RA, their molecular regulation and their translational potential for developing novel protective and therapeutic strategies in the clinic.
Practitioners of ancient societies from the time of Hippocrates and earlier recognized and treated the signs of inflammation, heat, redness, swelling, and pain with agents that block or inhibit ...proinflammatory chemical mediators. More selective drugs are available today, but this therapeutic concept has not changed. Because the acute inflammatory response is host protective to contain foreign invaders, much of today's pharmacopeia can cause serious unwanted side effects, such as immune suppression. Uncontrolled inflammation is now considered path‐ophysiologic and is associated with many widely occurring diseases such as cardiovascular disease, neurodegen‐erative diseases, diabetes, obesity, and asthma, as well as classic inflammatory diseases (e.g., arthritis and periodontal diseases). The inflammatory response, when self‐limited, produces a superfamily of chemical media‐tors that stimulate resolution of the response. Specialized proresolving mediators (SPMs), identified in recent years, are endogenous mediators that include the n‐3–derived families resolvins, protectins, and maresins, as well as arachidonic acid–derived (n‐6) lipoxins, which promote resolution of inflammation, clearance of microbes, reduction of pain, and promotion of tissue regeneration via novel mechanisms. Aspirin and statins have a positive impact on these resolution pathways, producing epimeric forms of specific SPMs, whereas other drugs can disrupt timely resolution. In this article, evidence from recent human and preclinical animal studies is reviewed, indicating that SPMs are physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. The findings suggest that it is time to challenge current treatment practices—namely, using inhibitors and antagonists alone—and to develop immunoresolvents as agonists to test resolution pharmacology and their role in catabasis for their therapeutic potential. —Serhan, C. N. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J. 31, 1273–1288 (2017) www.fasebj.org
The Atlas of Inflammation Resolution (AIR) Serhan, Charles N.; Gupta, Shailendra K.; Perretti, Mauro ...
Molecular aspects of medicine,
08/2020, Volume:
74
Journal Article
Peer reviewed
Open access
Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to ...homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de
The acute inflammatory response is host-protective to contain foreign invaders. Many of today's pharmacopeia that block pro-inflammatory chemical mediators can cause serious unwanted side effects ...such as immune suppression. Uncontrolled inflammation is now considered a pathophysiologic basis associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity and asthma, as well as the classic inflammatory diseases, e.g. arthritis, periodontal diseases. The inflammatory response is designated to be a self-limited process that produces a superfamily of chemical mediators that stimulate resolution of inflammatory responses. Specialized proresolving mediators (SPM) uncovered in recent years are endogenous mediators that include omega-3-derived families resolvins, protectins and maresins, as well as arachidonic acid-derived (n-6) lipoxins that stimulate and promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via novel mechanisms. Here, we review recent evidence from human and preclinical animal studies, together with the structural and functional elucidation of SPM indicating the SPM as physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. These results suggest that it is time to develop immunoresolvents as agonists for testing resolution pharmacology in nutrition and health as well as in human diseases and during surgery.
Mediator is an essential, large, multisubunit, transcriptional co-activator highly conserved across eukaryotes. Mediator interacts with gene-specific transcription factors at enhancers as well as ...with the RNA polymerase II (RNAPII) transcription machinery bound at promoters. It also interacts with several other factors involved in various aspects of transcription, chromatin regulation, and mRNA processing. Hence, Mediator is at the nexus of RNAPII transcription, regulating its many steps and connecting transcription with co-transcriptional events. To achieve this flexible role, Mediator, which is divided into several functional modules, reorganizes its conformation and composition while making transient contacts with other components. Here, we review the mechanisms of action of Mediator and propose a unifying model for its function.
Mediator is implicated in most aspects of gene expression, including nearly all steps of the transcription reaction, in addition to mRNA processing, higher-order chromatin organization, and genome stability.
The dynamic composition and structure of Mediator have recently begun to be elucidated through both structural work and in vivo protein–DNA interaction mapping.
The Kinase module has both positive and negative roles in gene expression regulation.
Accumulating evidence suggests a role for inflammation in the pathophysiology of epilepsy.
We performed a systematic review and meta-analysis of studies that investigated inflammatory mediators in ...human epilepsy. Studies reporting on inflammatory mediators in serum, cerebrospinal fluid or brain tissue of epilepsy patients were included. Studies comparing patients to controls were included in a meta-analysis.
66 articles reporting on 1934 patients were included. IL-1ra, IL-1β, IL-6, IL-10, IFN-γ and TNF-α were the most extensively investigated proteins. Elevated levels for IL-1ra, IL-1β, IL-6 and CXCL8/IL-8 were reported in several different epilepsy etiologies and media, while other proteins were specifically increased for one etiology. IL-1α, IL-7 and IL-13, as well as the chemokines CCL2-5, -19 and -22, were increased exclusively in brain tissue. In an aggregate meta-analysis, we found significantly different protein levels for serum IL-6, IL-17 and CSF IL-1β and IL-10.
Inflammatory pathways are involved in epilepsy. Future studies may further clarify their role, and prove potential of targeted anti-inflammatory treatment.
Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40% of colorectal cancer patients. The hallmarks of systemic inflammation include an increased production of ...proinflammatory cytokines and acute phase proteins that enter the circulation. While the low-level systemic inflammation is often clinically silent, its consequences are many and may ultimately lead to chronic cancer-associated wasting, cachexia. In this review, we discuss the pathogenesis of cancer-related systemic inflammation, explore the role of systemic inflammation in promoting cancer growth, escaping antitumor defense, and shifting metabolic pathways, and how these changes are related to less favorable outcome.
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