Prostanoids and Resolution of Inflammation – Beyond the Lipid-Mediator Class Switch

Bioactive lipid mediators play a major role in regulating inflammatory processes. Herein, early pro-inflammatory phases are characterized and regulated by prostanoids and leukotrienes, whereas specialized pro-resolving mediators (SPM), including lipoxins, resolvins, protectins, and maresins, dominate during the resolution phase. While pro-inflammatory properties of prostanoids have been studied extensively, their impact on later phases of the inflammatory process has been attributed mainly to their ability to initiate the lipid-mediator class switch towards SPM. Yet, there is accumulating evidence that prostanoids directly contribute to the resolution of inflammation and return to homeostasis. In this mini review, we summarize the current knowledge of the resolution-regulatory properties of prostanoids and discuss potential implications for anti-inflammatory, prostanoid-targeted therapeutic interventions.

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GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Cells ◽

10.3390/cells9040820 ◽

2020 ◽

Vol 9 (4) ◽

pp. 820 ◽

Cited By ~ 8

Author(s):

Leonie Hoffmeister ◽

Mareike Diekmann ◽

Korbinian Brand ◽

René Huber

Keyword(s):

Immune Cells ◽

Tissue Repair ◽

Inflammatory Cytokine ◽

Inflammatory Process ◽

Viral Infections ◽

Current Knowledge ◽

Resolution Of Inflammation ◽

Multiple Levels ◽

Experimental Disease

GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted.

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The Role of Innate Immunity and Bioactive Lipid Mediators in COVID-19 and Influenza

Frontiers in Physiology ◽

10.3389/fphys.2021.688946 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sabina Sahanic ◽

Judith Löffler-Ragg ◽

Piotr Tymoszuk ◽

Richard Hilbe ◽

Egon Demetz ◽

...

Keyword(s):

Immune Cells ◽

Current Knowledge ◽

Influenza Virus Infection ◽

Lipid Mediators ◽

Innate Immune ◽

Lipid Mediator ◽

Type I ◽

Innate Immune Cells ◽

Rna Seq

In this review, we discuss spatiotemporal kinetics and inflammatory signatures of innate immune cells specifically found in response to SARS-CoV-2 compared to influenza virus infection. Importantly, we cover the current understanding on the mechanisms by which SARS-CoV-2 may fail to engage a coordinated type I response and instead may lead to exaggerated inflammation and death. This knowledge is central for the understanding of available data on specialized pro-resolving lipid mediators in severe SARS-CoV-2 infection pointing toward inhibited E-series resolvin synthesis in severe cases. By investigating a publicly available RNA-seq database of bronchoalveolar lavage cells from patients affected by COVID-19, we moreover offer insights into the regulation of key enzymes involved in lipid mediator synthesis, critically complementing the current knowledge about the mediator lipidome in severely affected patients. This review finally discusses different potential approaches to sustain the synthesis of 3-PUFA-derived pro-resolving lipid mediators, including resolvins and lipoxins, which may critically aid in the prevention of acute lung injury and death from COVID-19.

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Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

Clinical Science ◽

10.1042/cs20191213 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2243-2262

Author(s):

Danlin Liu ◽

Gavin Richardson ◽

Fehmi M. Benli ◽

Catherine Park ◽

João V. de Souza ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Cardiovascular System ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Molecular Targets ◽

Therapeutic Interventions ◽

Low Grade ◽

Cardiovascular Research ◽

Inflammatory Processes ◽

Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

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Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

Current Vascular Pharmacology ◽

10.2174/1570161118666200616144512 ◽

2020 ◽

Vol 19 (2) ◽

pp. 176-192

Author(s):

Samantha Bedell ◽

Janine Hutson ◽

Barbra de Vrijer ◽

Genevieve Eastabrook

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Maternal Obesity ◽

Environmental Changes ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Placental Development ◽

Exchange Site ◽

And Function

: Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

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Immune Actions on the Peripheral Nervous System in Pain

International Journal of Molecular Sciences ◽

10.3390/ijms22031448 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1448

Author(s):

Jessica Aijia Liu ◽

Jing Yu ◽

Chi Wai Cheung

Keyword(s):

Chronic Pain ◽

Nervous System ◽

Peripheral Nervous System ◽

Immune Cells ◽

Molecular Mechanisms ◽

Process Integration ◽

Current Knowledge ◽

Therapeutic Strategies ◽

Lipid Mediators ◽

Cellular Changes

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.

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From Vietnamese plants to a biflavonoid that relieves inflammation by triggering the lipid mediator class switch to resolution

Acta Pharmaceutica Sinica B ◽

10.1016/j.apsb.2021.04.011 ◽

2021 ◽

Author(s):

Tran Thị Van Anh ◽

Alilou Mostafa ◽

Zhigang Rao ◽

Simona Pace ◽

Stefan Schwaiger ◽

...

Keyword(s):

Lipid Mediator ◽

Class Switch

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Cancer-Associated Fibroblasts as Players in Cancer Development and Progression and Their Role in Targeted Radionuclide Imaging and Therapy

Cancers ◽

10.3390/cancers13051100 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1100

Author(s):

Sofia Koustoulidou ◽

Mark W. H. Hoorens ◽

Simone U. Dalm ◽

Shweta Mahajan ◽

Reno Debets ◽

...

Keyword(s):

Current Knowledge ◽

Tumour Microenvironment ◽

Therapeutic Interventions ◽

Great Promise ◽

Cancer Associated Fibroblasts ◽

Functional Heterogeneity ◽

Radioligand Therapy ◽

Targeted Interventions ◽

Theranostic Applications ◽

Complex Origin

Cancer Associated Fibroblasts (CAFs) form a major component of the tumour microenvironment, they have a complex origin and execute diverse functions in tumour development and progression. As such, CAFs constitute an attractive target for novel therapeutic interventions that will aid both diagnosis and treatment of various cancers. There are, however, a few limitations in reaching successful translation of CAF targeted interventions from bench to bedside. Several approaches targeting CAFs have been investigated so far and a few CAF-targeting tracers have successfully been developed and applied. This includes tracers targeting Fibroblast Activation Protein (FAP) on CAFs. A number of FAP-targeting tracers have shown great promise in the clinic. In this review, we summarize our current knowledge of the functional heterogeneity and biology of CAFs in cancer. Moreover, we highlight the latest developments towards theranostic applications that will help tumour characterization, radioligand therapy and staging in cancers with a distinct CAF population.

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Cellular and Molecular Players in the Interplay between Adipose Tissue and Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22031359 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1359

Author(s):

Francesca Reggiani ◽

Paolo Falvo ◽

Francesco Bertolini

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Metabolic Disorders ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Preclinical Research ◽

The World ◽

Adipose Cells

The incidence and severity of obesity are rising in most of the world. In addition to metabolic disorders, obesity is associated with an increase in the incidence and severity of a variety of types of cancer, including breast cancer (BC). The bidirectional interaction between BC and adipose cells has been deeply investigated, although the molecular and cellular players involved in these mechanisms are far from being fully elucidated. Here, we review the current knowledge on these interactions and describe how preclinical research might be used to clarify the effects of obesity over BC progression and morbidity, with particular attention paid to promising therapeutic interventions.

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Nuclear receptor Nur77: its role in chronic inflammatory diseases

Essays in Biochemistry ◽

10.1042/ebc20210004 ◽

2021 ◽

Author(s):

Sanne C. Lith ◽

Carlie J.M. de Vries

Keyword(s):

Nuclear Receptor ◽

Inflammatory Disease ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Types ◽

Experimental Models ◽

Therapeutic Interventions ◽

Alternative Mechanism ◽

Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

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Human and Mouse Eosinophils Differ in Their Ability to Biosynthesize Eicosanoids, Docosanoids, the Endocannabinoid 2-Arachidonoyl-glycerol and Its Congeners

Cells ◽

10.3390/cells11010141 ◽

2022 ◽

Vol 11 (1) ◽

pp. 141

Author(s):

Anne-Sophie Archambault ◽

Julyanne Brassard ◽

Émilie Bernatchez ◽

Cyril Martin ◽

Vincenzo Di Marzo ◽

...

Keyword(s):

Healthy Subjects ◽

Biosynthetic Pathway ◽

Lipid Mediators ◽

Lipid Mediator ◽

Bioactive Lipids ◽

Eosinophilic Asthma ◽

Asthmatic Response ◽

Pharmacological Targets ◽

Arachidonoyl Glycerol ◽

Human And Mouse

High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma. However, many pinpointed targets in mice did not translate into clinics, underscoring that key differences exist between the two species. In this study, we compared the ability of human (h) and mouse (m) EOS to biosynthesize key bioactive lipids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). hEOS were isolated from the blood of healthy subjects and mild asthmatics, while mEOSs were differentiated from the bone marrow. EOSs were treated with fatty acids and lipid mediator biosynthesis assessed by LC-MS/MS. We found that hEOS biosynthesized leukotriene (LT) C4 and LTB4 in a 5:1 ratio while mEOS almost exclusively biosynthesized LTB4. The biosynthesis of the 15-lipoxygenase (LO) metabolites 15-HETE and 12-HETE also differed, with a 15-HETE:12-HETE ratio of 6.3 for hEOS and 0.727 for mEOS. EOS biosynthesized some specialized pro-resolving mediators, and the levels from mEOS were 9-times higher than those of hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and its congeners from EPA and DHA, a biosynthetic pathway that was up to ~100-fold less prominent in mEOS. Our data show that hEOS and mEOS biosynthesize the same lipid mediators but in different amounts. Compared to asthmatics, mouse models likely have an amplified involvement of LTB4 and specialized pro-resolving mediators and a diminished impact of the endocannabinoid 2-arachidonoyl-glycerol and its congeners.

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