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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

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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*,† (LPA) is a pleiotropic mol- but not saturated (16:0 and 18:0), LPA (2), possibly ecule with potent effects on growth and motility. reflecting affinity for the cell surface 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 previously be produced by the action of 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 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 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 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 , 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 . 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 –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, D; MS, mass spectrometry; Received for publication October 23, 2013. Accepted for publication December 5, 2013. S1P, -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 , 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). 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, , 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. range, one possibility is that LPA receptors on circulating LPA can also bind to non-GPCR targets that are both ex- leukocytes or endothelial cells (ECs) are continually engaged. tracellular (e.g., RAGE) and intracellular (e.g., the nuclear Tonic engagement would lead to receptor desensitization and receptor PPAR-g and the cation channel TRPV1) (19–21). is difficult to reconcile with the proinflammatory/barrier dis- Although most canonical LPA GPCRs demonstrate prefer- ruptive effects of LPA on EC subsets when studied in vitro (15). ential binding to longer-chain-length unsaturated species, LPA likely circulates in microparticles or bound to albumin PPAR-g is only activated by unsaturated LPA species and is The Journal of Immunology 853 critically important for the effects of LPA on vascular One model suggests that locally generated LPA provides remodeling (20). Very little is known about the role of these a chemokinetic “boost” that facilitates exit from the noncanonical LPA receptors in immune cells. circulation and entry into lymph nodes along chemotactic gra- dients established by canonical lymph node–associated . LPA receptors are expressed by T cells The receptors involved in LPA-dependent T cell emigration LPA enhances the motility of human and mouse T cells in from HEVs are not known. A second model suggests that the vitro, although generally not in a directed manner (22–24). ATX/LPA axis regulates T cell homing indirectly by acting LPA also induces actin remodeling, uropod formation, and on HEV ECs. These data are supported by the observations T cell polarization on ICAM-1– and CCL21-coated chambers that HEV ECs express LPA1 and LPA4, LPA induces changes (24, 25). The T cell LPA receptors involved in these responses in the EC cytoskeleton, and a potent small molecule inhibitor are not known. LPA enhances the invasion of T lymphoma of ATX (HA130) did not affect lymphocyte accumulation at cells into tissue substrates, which, in the case of Jurkat T cells, HEVs but did attenuate their extravasation (25, 28, 35). Fur- depended on LPA2 (22, 23). LPA5 (GPR92) mRNA is thermore, using novel imaging approaches, Bai et al. (35) abundant in the small intestine, especially in CD8+ intra- demonstrated that, after lymphocytes infiltrate the EC layer, epithelial lymphocytes (26, 27), but the function of this re- migration across the HEV basal lamina required LPA. These ceptor is unknown. More research using gene-targeted mice data suggest that by inducing EC motility and shape change, and LPA receptor antagonists should help to clarify the role LPA allows lymphocytes to detach from the HEV basal lamina of LPA in T cell migration in the near future. and migrate into the lymph node parenchyma. Downloaded from

Autotaxin is expressed by high endothelial venules: Role in T cell Manipulating the ATX/LPA axis with pathway antagonists homing If the model proposed above is correct, then antagonists of In 2008, two reports (24, 28) revealed that ATX is consti- the ATX/LPA axis should inhibit steady-state lymphocyte tutively expressed and released from lymphoid organ high trafficking, whereas should have the opposite effects. endothelial venule (HEV) ECs. These and other studies Experimental evidence supporting the ability of ATX/LPA http://www.jimmunol.org/ challenged the notion that ATX was a trans-membrane pro- antagonists to inhibit lymphocyte homing into lymphoid tein and suggested that secreted ATX could act at a distance organs is starting to emerge, but we have no evidence that this from its site of production. One working model suggests that affects generation of Ag-specific immunity. For example, in- ATX is secreted into the lumen of the HEV where it binds to cubating T cells with an inactive form of ATX (T120A), which receptors on nearby cells, hydrolyzes the abundant LPC found probably acts in a dominant negative manner and competes in the plasma, and generates a locally restricted high con- with endogenous ATX, attenuated cell homing to lymph nodes centration of LPA. Kanda et al. (24) showed that ATX can following adoptive transfer, as demonstrated by reduction of bind to -activated human lymphocytes in a b1- T cells in the vicinity of HEVs 15 min later (24). Another small by guest on September 27, 2021 –dependent manner; interestingly, binding to mouse molecule inhibitor of ATX (HA130) specifically attenuated lymphocytes appeared to be integrin independent. Subse- lymphocyte extravasation (discussed above) (25). However, an quently, Zhang et al. (25) found that polarized T cells possess anti-ATX mAb administered i.p. that depleted plasma ATX did Mn+-activatable receptors for ATX that are localized at the not inhibit lymphocyte trafficking to lymph nodes or the leading edge. Because activated platelets can produce and bind spleen, suggesting that ATX in the circulation is not as im- ATX (4, 29), as well as participate in lymphocyte trafficking at portant as locally produced ATX at the HEVs (28). BrP-LPA HEVs (30, 31), an additional possibility is that platelets con- is a dual inhibitor of ATX and LPA receptors, and local ad- tribute to ATX-dependent LPA production in lymphoid organs. ministration of this compound diminished the trafficking of The crystal structure of ATX was recently solved and has adoptively transferred lymphocytes into lymph nodes 30 min provided insights into how this molecule may function in vivo later (35). Ki16425 is an LPA with se- (32, 33). In addition to phosphodiesterase domains, ATX lectivity for LPA1 and LPA3. When injected into the footpad contains N-terminal cysteine-rich somatomedin-B–like domains of mice, Ki16425 did not significantly reduce T cell migration and a C-terminal nuclease domain. Integrin binding by ATX in vitro or lymphocyte trafficking to lymph nodes (35). These appears to involve the somatomedin-B–like domains in an Arg- data are consistent with the possibility that T lymphocyte Gly-Asp–independent manner (32). A splice variant of ATX, LPA2 is important for lymph node entry, but they also sup- termed “ATXa,” was recently shown to bind heparan sulfate port a role for LPA acting on ECs in an LPA1/3-independent proteoglycans (34). One unusual feature was the existence of manner. Newer and more stable antagonists of ATX and LPA a hydrophobic pocket and nearby channel that was large enough receptors are actively being developed, with the hope that these to accommodate a phospholipid with only a single acyl side will demonstrate efficacy in cancer therapeutics (10). These chain. In additional to helping explain the preference of ATX for compounds will also be useful tools to study the ATX/LPA axis lysolipid substrates, these structural features indicate that ATX in the initiation and regulation of adaptive immunity. How- can act as a lipid carrier and suggested a model in which integrin ever, clinical trials of ATX antagonists in cancer patients will or substrate binding induces a conformational change, allowing need to be monitored carefully for untoward effects on the ATX to release bound LPA to target receptors on nearby cells. A immune system, including immunosuppression. Is it possible corollary of this model is that tethering of ATX restricts newly to boost Ag-specific immunity by activating the ATX/LPA axis? generated bioactive LPA to an extremely precise location in vivo, Currently, there is little experimental evidence to support this such as HEVs. possibility, but future studies investigating whether enhancing It is unknown whether ATX-generated LPA acts on T cells, ATX activity or LPA production could boost generation of HEV ECs, or both, and different models have been proposed. adaptive immunity seem worthwhile. 854 BRIEF REVIEWS: ATX/LPA REGULATE LYMPHOCYTE HOMING AND INFLAMMATION

Regardless of mechanisms involved, the possibility that LPA for this receptor in LPA-directed migration (2). In addition to promotes steady-state T recirculation through lymph nodes inducing immature DC motility, LPA can influence DC and secondary lymphoid organs is an exciting new direction function. LPA inhibited the production of IL-12 and TNF-a and complements the now well-recognized role for the related from LPS-stimulated DCs in a pertussis toxin–insensitive sphingolipid S1P in lymphocyte egress (36). Future studies in manner (53). We recently reported that LPA inhibited LPS- which LPA receptor expression can be regulated in a cell type– dependent DC activation, at least in part, in an LPA2- specific manner will be needed to determine the relative im- dependent manner and, furthermore, that LPA2-deficient portance of LPA-induced T cell motility, endothelial shape DCs were hyperactive after adoptive transfer in vivo (55). change, or both in regulating T cell homing. It will be in- Consequently, the effects of LPA on DCs are complex and teresting in future studies to determine whether receptor de- influenced by LPA species (discussed above), DC activation sensitization influences the effects of LPA on T cell migration, status, and receptors engaged. By inducing the mobility of similar to the effects of GRK2 on S1PR1 (37). Several other both naive T cells and immature DCs, LPA would seem to be unanswered questions remain that should be readily ad- well-suited to promote DC:T interactions in lymphoid organs dressable in the coming years. For example, what are the and the initiation of adaptive immune responses. concentrations of LPA in afferent or efferent lymphatics? ATX is also upregulated during inflammation: lessons from asthma Does the ATX/LPA axis regulate T cell homing in a subset- models specific manner? What receptors are involved in this process?

Do ATX/LPA regulate recirculation or lymph node entry of In addition to lymph node HEVs, ATX is constitutively Downloaded from other immune cells besides T cells? Future research into these expressed in a few other tissues in adult mice and humans, questions should enhance our understanding of how ATX and including adipocytes and the lung (24, 28, 56–58). Interest- LPA regulate adaptive immunity in vivo. ingly, ATX was recently identified in mice in a screen for genes affecting lung development (59). Constitutive expres- LPA effects on DCs and other cell types sion of ATX in the lung may help to explain the fact that LPA

In addition to lymphocytes, other immune cells express LPA is a normal component of epithelial lining fluids (60). The http://www.jimmunol.org/ receptors and are influenced by LPA, including NK cells, mast function of LPA in the lung at steady-state is not known, but cells, eosinophils, and B cells (summarized in Table I) (38–52). it may play a role in maintaining homeostasis by promoting LPA induces of immature mouse bone marrow– epithelial barrier integrity (61). Interestingly, both wild-type derived DCs, which involves pertussis toxin–sensitive recep- and lyso-PLD mutant ATX induce airway epithelial migra- tors. Interestingly, this effect is lost in DCs matured in the tion, suggesting that some of the effects of ATX in the airway presence of LPS (2, 53). LPS does not induce major changes are independent of LPA generation (62). in LPA receptor mRNA or protein expression in cell lysates ATX expression and activity increase in different disease (2, 53, 54), suggesting that coupling or LPA re- states, which suggest that the ATX/LPA axis may play a broader by guest on September 27, 2021 ceptor surface expression is inhibited during DC maturation. role in inflammation in general. For example, ATX is inducibly Immature DCs derived from LPA3 gene-targeted mice do not expressed on ECs in the inflamed pancreas (28) and in lung migrate to LPA in vitro, demonstrating a critical requirement epithelial cells following bleomycin exposure (63). Excitingly,

Table I. Effects of LPA on different cell types

LPA Receptors LPA Species Cell Type Implicated Summary of Findings (Concentration) Ref. NK LPA1, 2, 3 Chemotaxis; mobilization of Ca2+ in activated cells; enhanced 18:1 (1–10 mM) (38) IFN-g secretion; LPAR detected by flow cytometry LPA2 Inhibited release of perforin and cytotoxic activity; enhances 14:0 (0.02–20 mM) (39) cAMP levels and activates PKA Mast cells LPA1, 2, 3, 4 (human); induces proliferation and differentiation 18:1 (5 mM) (40) (mRNA) NA Activates mast cells; causes tryptase release and vascular leakage LPA gel (41) in a –dependent manner in mice LPA1, 3 Histamine release, inhibited by DGPP 18:1 (10 mg/ml) (42) LPA2 Production of MIP-1b, IL-8, MCP-1 in an IL-4–dependent 18:1 and 18:2 (1–50 mM) (43) manner LPA5 (mRNA) MIP-1b release (human) 18:1 (1–5 mM) (44) Neutrophils NA Infiltration of neutrophils in BAL fluid of guinea pigs in 18:1 (1–10 mg/ml) (45) Rho/ROCK-dependent manner LPA1, 2 (mRNA Greater chemotaxis of neutrophils from pneumonia patients LPA (0.1–1 mM) (46) and protein) compared to controls NA Degranulation, phosphatidic acid production 18:1 (10–40 mM) (47) / NA Survival factor for murine macrophages via PI3K 18:1 (7.7 mM) (48) monocytes NA Upregulated IL-1b in mouse and human macrophages NA (49) NA Monocyte migration to MCP-1 via Ca2+-independent NA (50) at the leading edge B cells LPA2 (mRNA) B lymphoblast growth factor; MAPK activation; Ig production 18:1 (0.1–1 mM) (51) Lymphatic LPA2 Proliferation and lymphangiogenesis via IL-8 18:1 (0.5–10 mM) (52) endothelium NA, Not available. The Journal of Immunology 855 inhibition or genetic deletion of ATX significantly attenuated vation (55). These data are in keeping with other potentially lung fibrosis, supporting a crucial role for LPA in these models inhibitory effects of LPA, including suppression of DC (63, 64). ATX expression is upregulated in synovial cells from production discussed above (53), protection from patients with rheumatoid arthritis, and recent studies firmly endotoxin-induced inflammation and neutrophilia (61, 78), implicated ATX-derived LPA in the pathogenesis of inflam- induction of the decoy receptor IL-13Ra2onepithelialcells matory arthritis (65–68). The signals that regulate both steady- (79), and stimulation of avb6 integrin–mediated activation state and inducible ATX expression require further study. In of TGF-b (80). Taken together, these data point to both monocytic THP1 cells, Li and Zhang (69) reported that ATX proinflammatory and potentially anti-inflammatory effects of mRNA and protein were induced by the TLR4 LPS but LPA in asthma, depending on the timing and context of its constitutive ATX expression in HEVs was independent of the production. Under conditions of acute inflammation, such as TLR adaptor MyD88 (28). following allergen challenge in allergic human subjects or mouse Growing evidence points to an important role for the ATX/ models of repetitive allergen exposure, LPA may act alone or in LPA axis in mouse models of allergic airway inflammation and concert with other mediators to promote the recruitment or ac- humans with asthma. Using HPLC and tandem MS, we found tivation of inflammatory cell subsets. More chronically, LPA may that LPA is constitutively detectable in bronchoalveolar lavage play a regulatory role, and it is tempting to speculate that, over (BAL) fluids at baseline, but it increased significantly 18 h time, repeated cycles of LPA generation might contribute to following segmental allergen challenge of allergic human sub- airway remodeling in chronic asthma. jects (from 483 6 77 to 1506 6 358 nM) (60). Assuming an Downloaded from ∼100-fold dilution during BAL (70), we estimated that epi- Conclusions thelial lining fluid LPA levels in the lung are in micromolar New research will likely soon be forthcoming that will define range. Interestingly, the accumulation of LPA species after al- with greater precision the role of the ATX/LPA axis in im- lergen challenge was not uniform but was enriched in poly- mune and inflammatory diseases. It seems apparent that ATX unsaturated species, including 20:4 and 22:6 LPA (60). More and LPA have previously underappreciated roles in steady- recently, Park et al. (71) confirmed these findings and also state lymphocyte homing, but we need to understand how http://www.jimmunol.org/ effects on T cell migration translate into regulation of adaptive showed that 22:5 LPA was also enriched in BAL fluids after immunity. Newer-generation and more stable ATX antagonists allergen challenge. The function of polyunsaturated LPA in the will likely prove useful tools in this regard in the near future. In lung is not entirely clear. Although LPA can promote eosino- addition to their clinical efficacy in cancer, these agents may have phil chemotaxis in vitro (72), we found that LPA levels did not untoward effects on the immune system (e.g., immunosup- correlate with eosinophil influx 18 h after challenge (60), ar- pression), which will need to be monitored carefully. It will be guing that LPA was not a dominant eosinophilic chemo- interesting to determine whether gain-of-function approaches attractant in this model. It remains to be seen whether LPA that enhance ATX/LPA activity can be used to boost generation promotes the recruitment of leukocyte subsets or immature by guest on September 27, 2021 of immunity. More research is needed into the mechanisms and DCs to the lung. Using a novel ATX antagonist in a triple- consequences of ATX upregulation in inflammatory diseases. It allergen challenge mouse model of asthma, Park et al. (71) will be important to decipher whether the dominant action showed that LPA generation in the allergic lung was dependent of LPA in these models is in the regulation of cell motility/ on ATX activity and suggested, based on immunohistochemical migration, activation, or survival. Because both LPA and LPC analysis and cell culture experiments, that lung epithelial cells are involved in numerous metabolic pathways, it is tempting to and IL-4–stimulated macrophages were potential sources of speculate that these novel lysolipid compounds are at the in- ATX. Furthermore, some of the inflammatory effects of triple- tersection of and immunity. allergen challenge were attenuated in LPA2-deficient mice (71). Separate from its potential effects on cell migration, LPA has other functions and cellular targets relevant to the path- Disclosures ophysiology of asthma. For example, LPA can induce the dif- The authors have no financial conflicts of interest. ferentiation and activation of mast cells (40, 43, 44) (Table I), promote airway epithelial chemokine/cytokine production (73, 74), and augment airway smooth muscle cell growth and con- References tractility (75–77). The ability of LPA to induce airway epithelial 1. Sano, T., D. Baker, T. Virag, A. Wada, Y. Yatomi, T. Kobayashi, Y. Igarashi, and thymic stromal lymphopoietin production is noteworthy (74), G. Tigyi. 2002. Multiple mechanisms linked to platelet activation result in lyso- phosphatidic acid and sphingosine 1-phosphate generation in blood. J. Biol. Chem. given the crucial role for this cytokine in the initiation of Th2- 277: 21197–21206. dependent immunity. Although these studies suggest that LPA 2. Chan, L. C., W. Peters, Y. Xu, J. Chun, R. V. Farese, Jr., and S. Cases. 2007. LPA3 receptor mediates chemotaxis of immature murine dendritic cells to unsaturated may be a novel proinflammatory molecule and contribute to the lysophosphatidic acid (LPA). J. Leukoc. Biol. 82: 1193–1200. initiation of allergic airway inflammation, other results paint a 3. Fourcade, O., M. F. Simon, C. Viode´, N. Rugani, F. Leballe, A. Ragab, B. Fournie´, L. Sarda, and H. Chap. 1995. Secretory generates the novel lipid more nuanced picture. 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Using reciprocal phosphatidic acid and lysophosphatidylcholine formation in the plasma in vitro: bone marrow chimeras, this mapped, in part, to an inhibitory proposal of a plasma sample preparation method for laboratory testing of these . Anal. Biochem. 367: 20–27. effect of LPA2 on hematopoietic cells, and we concluded that 6. Umezu-Goto, M., Y. Kishi, A. Taira, K. Hama, N. Dohmae, K. Takio, T. Yamori, LPA has a previously unsuspected inhibitory role on DC acti- G. B. Mills, K. Inoue, J. Aoki, and H. Arai. 2002. Autotaxin has lysophospholipase 856 BRIEF REVIEWS: ATX/LPA REGULATE LYMPHOCYTE HOMING AND INFLAMMATION

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