Autotaxin and chronic inflammatory diseases

Magkrioti, Christiana; Galaris, Apostolos; Kanellopoulou, Paraskevi; Stylianaki, Elli-Anna; Kaffe, Eleanna; Aidinis, Vassilis

doi:10.1016/j.jaut.2019.102327

Cited by 72 publications

(86 citation statements)

References 129 publications

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“…On the contrary, systemic levels of ATX, in these same mice, has been shown to affect obesity-driven cardiomyocyte dysfunction [36] and hepatic steatosis [37], both involving deregulated insulin-glucose homeostasis. Therefore, plasma ATX, where 38-50% is thought to derive from the adipose tissue [38,39], does affect tissues/organs with a highly active metabolic rate, consistent with the characterization of ATX as an adipokine [40]. Additional plasma ATX has been suggested to derive from the endothelial cells of high endothelial venules (HEV), reported to modulate lymphocyte trafficking in lymphoid organs [12,41,42].…”

Section: Discussionsupporting

confidence: 66%

Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis

et al. 2020

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Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signaling lysophospholipid. ATX and LPA signaling have been incriminated in the pathogenesis of different chronic inflammatory diseases and various types of cancer. In this report, deregulated ATX and LPA levels were detected in the spinal cord and plasma of mice during the development of experimental autoimmune encephalomyelitis (EAE). Among the different sources of ATX expression in the inflamed spinal cord, F4/80 + CD11b + cells, mostly activated macrophages and microglia, were found to express ATX, further suggesting an autocrine role for ATX/LPA in their activation, an EAE hallmark. Accordingly, ATX genetic deletion from CD11b + cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.

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Section: Discussionsupporting

confidence: 66%

Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis

et al. 2020

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“…As previously discussed, physiological upregulation of ATX occurs as part of acute inflammation in wound healing and then dissipates after tissue repair is completed. If inflammation is not resolved, chronic activation of ATX-LPA-inflammatory signaling and the wound healing response becomes maladaptive [30,32] in diseases such as pulmonary fibrosis, cirrhosis, rheumatoid arthritis, inflammatory bowel disease, and cancers [24,48]. Many inflammatory conditions are accompanied by fibrosis, a process driven through LPAR1 signaling and further mediated through inflammatory cytokines [49][50][51][52][53][54][55][56][57][58][59][60][61].…”

Section: Maladaptive Effects Of Excessive Atx Secretion and Lpa Signamentioning

confidence: 99%

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

Benesch

Tang

Brindley

2020

Cancers

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After a decade of intense preclinical investigations, the first in-class autotaxin inhibitor, GLPG1690, has entered Phase III clinical trials for idiopathic pulmonary fibrosis. In the intervening time, a deeper understanding of the role of the autotaxin–lysophosphatidate (LPA)–lipid phosphate phosphatase axis in breast cancer progression and treatment resistance has emerged. Concordantly, appreciation of the tumor microenvironment and chronic inflammation in cancer biology has matured. The role of LPA as a central mediator behind these concepts has been exemplified within the breast cancer field. In this review, we will summarize current challenges in breast cancer therapy and delineate how blocking LPA signaling could provide novel adjuvant therapeutic options for overcoming therapy resistance and adverse side effects, including radiation-induced fibrosis. The advent of autotaxin inhibitors in clinical practice could herald their applications as adjuvant therapies to improve the therapeutic indexes of existing treatments for breast and other cancers.

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“…Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids [ 1 ], where it catalyzes the hydrolysis of lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) [ 2 , 3 ]. Although matricellular properties have been suggested for ATX, most of the reported effects of ATX are attributed to extracellular LPA production.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

Magkrioti

Kaffe

Stylianaki

et al. 2020

IJMS

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Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids, largely responsible for extracellular lysophosphatidic acid (LPA) production. LPA is a bioactive growth-factor-like lysophospholipid that exerts pleiotropic effects in almost all cell types, exerted through at least six G-protein-coupled receptors (LPAR1-6). Increased ATX expression has been detected in different chronic inflammatory diseases, while genetic or pharmacological studies have established ATX as a promising therapeutic target, exemplified by the ongoing phase III clinical trial for idiopathic pulmonary fibrosis. In this report, we employed an in silico drug discovery workflow, aiming at the identification of structurally novel series of ATX inhibitors that would be amenable to further optimization. Towards this end, a virtual screening protocol was applied involving the search into molecular databases for new small molecules potentially binding to ATX. The crystal structure of ATX in complex with a known inhibitor (HA-155) was used as a molecular model docking reference, yielding a priority list of 30 small molecule ATX inhibitors, validated by a well-established enzymatic assay of ATX activity. The two most potent, novel and structurally different compounds were further structurally optimized by deploying further in silico tools, resulting to the overall identification of six new ATX inhibitors that belong to distinct chemical classes than existing inhibitors, expanding the arsenal of chemical scaffolds and allowing further rational design.

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Autotaxin and chronic inflammatory diseases

Cited by 72 publications

References 129 publications

Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis

Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

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