TLR4 Receptor Induces 2-AG–Dependent Tolerance to Lipopolysaccharide and Trafficking of CB2 Receptor in Mast Cells

Espinosa-Riquer, Zyanya P; Ibarra-Sánchez, Alfredo; Vibhushan, Shamila; Bratti, Manuela; Charles, Nicolas; Blank, Ulrich; Rodrı́guez–Manzo, Gabriela; González-Espinosa, Claudia

doi:10.4049/jimmunol.1800997

Cited by 25 publications

(25 citation statements)

References 107 publications

(104 reference statements)

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“…Prolonged exposure to LPS results in toll-like receptor 4 (TLR4) activation, subsequent increase in 2-AG production in mast cells, CB2 activation, and finally hyporesponsivity of mast cells, called endotoxin tolerance (ET). CB2 antagonist, AM630, prevented ET in vitro [197], and thus CB2 antagonists may be studied further as a potential treatment for immunoparalysis.…”

Section: Inflammatory and Autoimmune Diseasesmentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

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Section: Inflammatory and Autoimmune Diseasesmentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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“…Non-lethal exposure to endotoxins such as LPS can render immune cells refractory to subsequent exposure and is characterized by reduced macrophage/monocyte cytokine (specifically TNF-α) production [87]. Development of this endotoxin tolerance in MCs has also been shown to be TLR-mediated and associated with a hyporesponsive phenotype [88]. Interestingly, endotoxin tolerance can be alternatively induced alongside TGF-β and IL-10 synthesis in monocytes in response to low levels of toxin; IL-10 suppresses NLRP3 activation during chronic exposure to LPS [85,89].…”

Section: Il-10 and Tgf-β1mentioning

confidence: 99%

Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

Lyons

Pullen

2020

IJMS

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Mast cells are often regarded through the lens of IgE-dependent reactions as a cell specialized only for anti-parasitic and type I hypersensitive responses. However, recently many researchers have begun to appreciate the expansive repertoire of stimuli that mast cells can respond to. After the characterization of the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis of mast cell activation—a pathway that is independent of the adaptive immune system—researchers are revisiting other stimuli to induce mast cell activation and/or subsequent degranulation independent of IgE. This discovery also underscores that mast cells act as important mediators in maintaining body wide homeostasis, especially through barrier defense, and can thus be the source of disease as well. Particularly in the gut, inflammatory bowel diseases (Crohn’s disease, ulcerative colitis, etc.) are characterized with enhanced mast cell activity in the context of autoimmune disease. Mast cells show phenotypic differences based on tissue residency, which could manifest as different receptor expression profiles, allowing for unique mast cell responses (both IgE and non-IgE mediated) across varying tissues as well. This variety in receptor expression suggests mast cells respond differently, such as in the gut where immunosuppressive IL-10 stimulates the development of food allergy or in the lungs where transforming growth factor-β1 (TGF-β1) can enhance mast cell IL-6 production. Such differences in receptor expression illustrate the truly diverse effector capabilities of mast cells, and careful consideration must be given toward the phenotype of mast cells observed in vitro. Given mast cells’ ubiquitous tissue presence and their capability to respond to a broad spectrum of non-IgE stimuli, it is expected that mast cells may also contribute to the progression of autoimmune disorders and other disease states such as metastatic cancer through promoting chronic inflammation in the local tissue microenvironment and ultimately polarizing toward a unique Th17 immune response. Furthermore, these interconnected, atypical activation pathways may crosstalk with IgE-mediated signaling differently across disorders such as parasitism, food allergies, and autoimmune disorders of the gut. In this review, we summarize recent research into familiar and novel pathways of mast cells activation and draw connections to clinical human disease.

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“…Mast cells and eosinophils express the majority of TLRs and induce the secretion of cytokines and chemokines initiating Th2 immune response [80,81]. TLR ligands stimulate macrophages and affect their production of endocannabinoids, whose function is to suppress TLR-mediated inflammatory response [139,140]. The effect of cannabinoids on macrophage function is a consequence of NF-κB inhibition [141].…”

Section: Rvd1mentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

et al. 2020

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The complexity of the pathogenetic mechanisms of the development of chronic inflammation in asthma determines its heterogeneity and insufficient treatment effectiveness. Nuclear transcription factors, which include peroxisome proliferatoractivated receptors, that is, PPARs, play an important role in the regulation of initiation and resolution of the inflammatory process. The ability of PPARs to modulate not only lipid homeostasis but also the activity of the inflammatory response makes them an important pathogenetic target in asthma therapy. At present, special attention is focused on natural (polyunsaturated fatty acids (PUFAs), endocannabinoids, and eicosanoids) and synthetic (fibrates, thiazolidinediones) PPAR ligands and the study of signaling mechanisms involved in the implementation of their anti-inflammatory effects in asthma. This review summarizes current views on the structure and function of PPARs, as well as their participation in the pathogenesis of chronic inflammation in asthma. The potential use of PPAR ligands as therapeutic agents for treating asthma is under discussion.

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TLR4 Receptor Induces 2-AG–Dependent Tolerance to Lipopolysaccharide and Trafficking of CB2 Receptor in Mast Cells

Cited by 25 publications

References 107 publications

A Guide to Targeting the Endocannabinoid System in Drug Design

A Guide to Targeting the Endocannabinoid System in Drug Design

Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

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