The Autotaxin−LPA Axis Emerges as a Novel Regulator of Lymphocyte Homing and Inflammation This information is current as Sara Knowlden and Steve N. Georas of September 27, 2021. J Immunol 2014; 192:851-857; ; doi: 10.4049/jimmunol.1302831 http://www.jimmunol.org/content/192/3/851 Downloaded from References This article cites 79 articles, 35 of which you can access for free at: http://www.jimmunol.org/content/192/3/851.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology The Autotaxin–LPA Axis Emerges as a Novel Regulator of Lymphocyte Homing and Inflammation Sara Knowlden* and Steve N. Georas*,† Lysophosphatidic acid (LPA) is a pleiotropic lipid mol- but not saturated (16:0 and 18:0), LPA (2), possibly ecule with potent effects on cell growth and motility. reflecting affinity for the cell surface receptor LPA3 (see Major progress has been made in recent years in deci- below). phering the mechanisms of LPA generation and how it LPA can be generated by multiple mechanisms, and a cur- acts on target cells. Most research has been conducted in rent challenge in the field is to relate different potential sources other disciplines, but emerging data indicate that LPA of LPA to biological activities in vivo. Extracellular LPA is has an important role to play in immunity. A key dis- thought to derive from at least two pathways. First, LPA can covery was that autotaxin (ATX), an enzyme previously be produced by the action of phospholipases on membrane Downloaded from implicated in cancer cell motility, generates extracellular microvesicles shed by activated platelets and erythrocytes (1, 3, 4). LPA from the precursor lysophosphatidylcholine. Steady- These pathways involve the direct hydrolysis of a fatty acid state ATX is expressed by only a few tissues, including moiety from membrane-derived phosphatidic acid. Second, high endothelial venules in lymph nodes, but inflamma- LPA can be generated from lysophosphatidylcholine (LPC) tory signals can upregulate ATX expression in differ- by removal of the choline moiety by the enzyme lysophospho- http://www.jimmunol.org/ ent tissues. In this article, we review current thinking lipase D (lyso-PLD). LPC is an intermediate in multiple lipid about the ATX/LPA axis in lymphocyte homing, as well metabolic pathways and circulates in the blood stream at a as in models of allergic airway inflammation and much higher concentration than LPA (5). These two pathways asthma. New insights into the role of LPA in regulating are not mutually exclusive, because certain phospholipases can produce LPC and other lysophospholipids from acti- immune responses should be forthcoming in the near vated platelets that are then cleaved by lyso-PLD to produce future. The Journal of Immunology, 2014, 192: LPA (4). 851–857. In 2002, the dominant lyso-PLD in serum was found to be an enzyme known as autotaxin (ATX) (6, 7). ATX had been by guest on September 27, 2021 discovered 10 years earlier by Liotta and colleagues (8), who Nomenclature and LPA generation were studying autocrine factors that promoted cancer cell ysophosphatidic acid (LPA) is a member of the gly- motility. Cloning of the autotaxin cDNA revealed domains cerophospholipid family, specifically a monoacylgly- similar to the ectonucleotide phosphodiesterase and pyro- L cerophosphate (GP1005, according to Lipid Maps phosphatase family, and ATX was designated ENPP2 (9). classification; http://www.lipidmaps.org). LPA has a three- However, the preferred substrates for ATX are not nucleotides carbon glycerol backbone with one acyl side chain that can but actually lysophospholipids, including LPC (4), and it is vary in length and saturation (Fig. 1). The prefix “lyso” indicates becoming clear that many functions previously ascribed to that only one fatty acid is attached to the phospholipid back- ATX can be explained by its ability to generate LPA. This is bone, and it distinguishes LPA from phosphatidic acid. The acyl especially true in the field of cancer biology, where the ATX/ group is usually located on the sn-1 carbon (i.e., 1-acyl-2- LPA axis is involved in the growth and metastasis of many hydroxy-sn-glycero-3-phosphate). In serum, most LPA species different tumors, and pathway antagonists are under active are polyunsaturated (e.g., 18:2 and 20:4) or monounsaturated development (10). (e.g., 18:1) (1). Emerging data indicate that the acyl moiety LPA is unstable in plasma, with a half-life , 5min,and affects the function of LPA, but this is a virtually unexplored area technically challenging to measure (11, 12). Experiments using in the immune system. One exception is the observation that lipid phosphate phosphatase (LPP)1 hypomorphic mice revealed immature mouse bone marrow–derived dendritic cells (DCs) that this enzyme is a major determinant of LPA instability preferentially migrate in vitro to unsaturated (18:1 and 20:4), in vivo (11). Interestingly, there appear to be tissue-specific *Department of Microbiology and Immunology, University of Rochester Medical Center, Abbreviations used in this article: ATX, autotaxin; BAL, bronchoalveolar lavage; DC, Rochester, NY 14642; and †Division of Pulmonary and Critical Care Medicine, Depart- dendritic cell; EC, endothelial cell; GPCR, G protein–coupled receptor; HEV, high ment of Medicine, University of Rochester Medical Center, Rochester, NY 14642 endothelial venule; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; LPP, lipid phosphate phosphatase; lyso-PLD, lysophospholipase D; MS, mass spectrometry; Received for publication October 23, 2013. Accepted for publication December 5, 2013. S1P, sphingosine-1 phosphate. This work was supported by National Institutes of Health Grants R01 HL071933 and P30 ES001247 (to S.N.G.) and T32 AI007285 (to S.K.). Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 Address correspondence and reprint requests to Dr. Steve N. Georas, University of Rochester Medical Center, 601 Elmwood Avenue, Box 692, Rochester, NY 14642. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302831 852 BRIEF REVIEWS: ATX/LPA REGULATE LYMPHOCYTE HOMING AND INFLAMMATION Downloaded from http://www.jimmunol.org/ FIGURE 1. Two main sources of LPA generation are from phosphatidic acid (left) via the action of phospholipases or by hydrolysis of the choline moiety of lysophosphatidylcholine (Lyso-PC), by ATX (also known as Lyso-PLD). Newly generated LPA can act on cell surface GPCRs or intracellular receptors, as indicated. Free LPA is rapidly degraded by lipid phosphate phosphatases into monoacyl glycerol. differences in LPP expression and activity, suggesting that ex- and other proteins, and it seems likely that this restricts its by guest on September 27, 2021 tracellularLPAmaybemorestableinsometissuesthanothers interaction with target receptors. (11). Relatively little is known about the stability of LPA in secondary lymphoid organs, although LPP expression is rela- LPA binds to different cell surface receptors and intracellular targets tively high in the spleen. The discovery that LPA interacted with specific cell surface LPA can be measured by colorimetric assays or mass receptors was a major advance. A detailed discussion of LPA spectrometry (MS), which has the advantage of detecting receptors is beyond the scope of this Brief Review, but this specific acyl side chains. A typical approach involves lipid topic was summarized recently (16). There are at least six G extraction, followed by HPLC and tandem MS in negative ion protein–coupled receptors (GPCR) that bind LPA and vary in mode, monitoring for the glycerol phosphoryl moiety (m/z = their tissue distribution. LPA1 (Edg2), LPA2 (Edg4), and 152.9) and parent compound acyl groups. To estimate LPA LPA3 (Edg7) belong to the Edg family, whereas LPA4–6 are concentrations, a closely related LPA species not normally more closely related to cell surface purinergic receptors (16, 17). present should be spiked into the original sample, extracted Other Edg receptor family members bind sphingosine-1 phos- and processed identically, and used to generate a standard phate (S1P), including S1P1 (Edg2). Signal transduction via curve. However, the efficiency of extraction of different LPA LPA receptors leads to activation of MAPKs, PI3K, and Rho species varies based on the sample and method used; at present, kinases, which affect cell activation, survival, and migration. the true bioactive concentrations of LPA in plasma or bio- This is a rapidly evolving field in which new candidate logical fluids is not clear. Plasma concentrations are probably receptors are being actively pursued; however, the lack of Abs inthe100-nMrangeandarehigherinwomenthaninmen directed against extracellular domains that detect surface ex- (5, 13, 14). In mice, similar variability in plasma LPA con- pression or antagonize LPA binding is a major hindrance. The centrations has been reported, reflecting the poorly under- availability of LPA receptor–deficient mice is starting to stood effects of age, gender, and strain (11). provide insights into the function of this molecule in vivo The function of circulating extracellular LPA is not known. (18), although more research is needed in models of innate Because the kDa of cell surface LPA receptors is in the nM and adaptive immunity.