Autotaxin in Pathophysiology and Pulmonary Fibrosis

Abstract

Lysophospholipid signaling is emerging as a druggable regulator of pathophysiological responses, and especially fibrosis, exemplified by the relative ongoing clinical trials in idiopathic pulmonary fibrosis (IPF) patients. In this review, we focus on ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2), or as more widely known Autotaxin (ATX), a secreted lysophospholipase D (lysoPLD) largely responsible for extracellular lysophosphatidic acid (LPA) production. In turn, LPA is a bioactive phospholipid autacoid, forming locally upon increased ATX levels and acting also locally through its receptors, likely guided by ATX's structural conformation and cell surface associations. Increased ATX activity levels have been detected in many inflammatory and fibroproliferative conditions, while genetic and pharmacologic studies have confirmed a pleiotropic participation of ATX/LPA in different processes and disorders. In pulmonary fibrosis, ATX levels rise in the broncheoalveolar fluid (BALF) and stimulate LPA production. LPA engagement of its receptors activate multiple G-protein mediated signal transduction pathways leading to different responses from pulmonary cells including the production of pro-inflammatory signals from stressed epithelial cells, the modulation of endothelial physiology, the activation of TGF signaling and the stimulation of fibroblast accumulation. Genetic or pharmacologic targeting of the ATX/LPA axis attenuated disease development in animal models, thus providing the proof of principle for therapeutic interventions.

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

“…Little is known on the regulation of ATX expression in the CNS and especially in the context of EAE. TNF and IL-6, intricately linked with EAE development [24,25], have been reported to stimulate ATX mRNA expression in different, non-CNS, cell types [6,36,37]; both TNF and IL-6 mRNA levels were found increased in EAE (Fig. S2A), suggesting that they could promote ATX expression in some cellular types, in a spatiotemporal manner.…”

“…Autotaxin (ATX, ENPP2) is a secreted glycoprotein widely present in biological fluids, catalyzing the extracellular hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a bioactive growth factor-like lysophospholipid [5][6][7].…”

[18F]PRIMATX, a New Positron Emission Tomography Tracer for Imaging of Autotaxin in Lung Tissue and Tumor‐Bearing Mice

“…In lung fibrosis, elevated local LPA levels have been shown to play a role in the migration, differentiation, and secretion profile of fibroblasts acting primarily via the G‐protein coupled lysophosphatidic acid receptor LPA1. Samples of lung tissue from idiopathic pulmonary fibrosis (IPF) patients show increased levels of ATX expression . Likewise, ATX is overexpressed in multiple human cancer cell lines .…”

Safety, Pharmacokinetics, and Pharmacodynamics of the Autotaxin Inhibitor GLPG1690 in Healthy Subjects: Phase 1 Randomized Trials

“…Autotaxin is a key enzyme responsible for the production of lysophosphatidic acid (LPA), a bioactive lipid that regulates a range of cellular processes . Autotaxin is widely expressed, with the highest mRNA levels found in adipose tissue, brain, testis, and ovary . In the lungs, autotaxin is expressed in bronchial epithelial cells and alveolar macrophages and is upregulated in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) .…”

“…1 Autotaxin is widely expressed, with the highest mRNA levels found in adipose tissue, brain, testis, and ovary. 2 In the lungs, autotaxin is expressed in bronchial epithelial cells and alveolar macrophages and is upregulated in lung tissue from patients with idiopathic pulmonary fibrosis (IPF). 3 Correspondingly, LPA levels are elevated in the bronchoalveolar fluid and exhaled breath condensate of patients with IPF.…”