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1529.Full.Pdf Intracellular Lipid Flux and Membrane Microdomains as Organizing Principles in Inflammatory Cell Signaling This information is current as Michael B. Fessler and John S. Parks of September 24, 2021. J Immunol 2011; 187:1529-1535; ; doi: 10.4049/jimmunol.1100253 http://www.jimmunol.org/content/187/4/1529 Downloaded from References This article cites 92 articles, 48 of which you can access for free at: http://www.jimmunol.org/content/187/4/1529.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 24, 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 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Intracellular Lipid Flux and Membrane Microdomains as Organizing Principles in Inflammatory Cell Signaling Michael B. Fessler* and John S. Parks† Lipid rafts and caveolae play a pivotal role in organiza- remodeling of raft lipid is not only necessary in many sig- tion of signaling by TLR4 and several other immune naling cascades, but that primary perturbations of raft lipid receptors. Beyond the simple cataloguing of signaling (e.g., cholesterol loading or unloading, raft coalescence) can events compartmentalized by these membrane microdo- also be sufficient initiating events to trigger protein signaling. mains, recent studies have revealed the surprisingly cen- Using the macrophage and, in particular, TLR signaling in tral importance of dynamic remodeling of membrane macrophages as a primary case in point, the dependence of lipid domains to immune signaling. Simple interven- inflammatory signaling upon cholesterol-loading conditions tions upon membrane lipid, such as changes in choles- and on the regulatory proteins that control homeostatic in- Downloaded from terol loading or crosslinking of raft lipids, are sufficient tracellular trafficking of cholesterol through rafts will be to induce micrometer-scale reordering of membranes highlighted. and their protein cargo with consequent signal trans- Lipid rafts and caveolae duction. In this review, using TLR signaling in the mac- rophage as a central focus, we discuss emerging evidence Lipid rafts are thought to be highly dynamic, nanoscale (i.e., , http://www.jimmunol.org/ that environmental and genetic perturbations of mem- 200 nm), cholesterol- and sphingolipid-enriched membrane brane lipid regulate protein signaling, illustrate how ho- microdomains, likely present in all eukaryotic cells, that meostatic flow of cholesterol and other lipids through compartmentalize select signaling and functional events. rafts regulates the innate immune response, and high- Although it is difficult to place a lower limit on their size in the resting state, and evidence indeed exists for “lipid shells” light recent attempts to harness these insights toward surrounding individual proteins in biological membranes therapeutic development. The Journal of Immunology, (2), rafts can also be driven to coalesce into more stable, 2011, 187: 1529–1535. micrometer-range domains through lipid–lipid, protein– lipid, and protein–protein interactions. The mechanisms by guest on September 24, 2021 ince the inception of the lipid raft hypothesis in 1997 underlying raft “coalescence” or “clustering,” however, in (1), a profusion of studies have reported roles for these many cases remain elusive. It is generally thought that the S cholesterol-enriched membrane microdomains in or- saturated acyl chains of raft sphingolipids and phospholipids ganization of cell signaling. As a crossroads for immunology, exhibit tight packing in a manner analogous to the liquid- biophysics, and lipid science, the raft field has suffered ordered domains observed in model membranes, and that this growing pains in terminology, technique, and interpretation. may account for their resistance to solubilization by cold Progressively refined imaging techniques continue to support nonionic detergents (e.g., Triton X-100). However, as de- the existence of lateral protein/lipid heterogeneities in bi- tergent can itself induce the formation of domains in mem- ological membranes (2, 3), but the precise nature, size, and branes (6), rafts should not be equated with “detergent- malleability of these microdomains remain a matter of debate. resistant membranes” (DRMs), nor can identification of A burgeoning field that has cataloged an increasing number of a protein in DRMs be taken as sufficient evidence for signaling events within rafts at the same time finds itself at risk assigning raft localization in vivo. Although good evidence of losing sight of the implications of this localization. In this supports the coexistence within cell membranes of heteroge- review, rather than focus on definitions of rafts/caveolae (for neous populations of lipid rafts, isolation of DRMs of discrete this, the reader is referred to recent scholarly reviews in Refs. composition with the use of different detergents should not 2, 4, 5), the objective is to synthesize and interpret emerging be considered as evidence for discrete raft domains in vivo. insights on how genetic and environmental modification of Caveolae are ∼60- to 80-nm cholesterol-enriched mem- raft lipid plays a fundamental role in determining immune brane invaginations whose flask-shaped morphology derives signaling and disease. The case will be made that dynamic from caveolin proteins, the expression of which suffices to *Laboratory of Respiratory Biology, National Institute of Environmental Health Scien- Address correspondence and reprint requests to Dr. Michael B. Fessler, National Institute ces, National Institutes of Health, Research Triangle Park, NC 27709; and †Section on of Environmental Health Sciences, 111 T.W. Alexander Drive, P.O. Box 12233, MD D2- Lipid Sciences, Department of Pathology and Biochemistry, Wake Forest School of 01, Research Triangle Park, NC 27709. E-mail address: [email protected] Medicine, Winston-Salem, NC 27157 Abbreviations used in this article: ABC, ATP-binding cassette; apo, apolipoprotein; Received for publication April 1, 2011. Accepted for publication May 10, 2011. DRM, detergent-resistant membrane; ER, endoplasmic reticulum; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA; mbCD, methyl-b-cyclo- This work was supported in part by the Intramural Research Program of the National dextrin; NPC1, Niemann–Pick C1; oxLDL, oxidized low-density lipoprotein; PUFA, Institutes of Health, National Institute of Environmental Health Sciences (Z01 polyunsaturated fatty acid; SR, scavenger receptor. ES102005) and by Grants HL094525 and HL049373 (to J.S.P.). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1100253 1530 BRIEF REVIEWS: MEMBRANE ORGANIZATION OF SIGNALING confer caveolar morphology (7). Caveolae are thought to re- in neutrophils (24). Imaging techniques with higher resolu- present a discrete, specialized subpopulation of membrane mi- tion than fluorescence microscopy will almost certainly be re- crodomains, and thus should not be simply equated with quired to properly characterize raft colocalization and co- lipid rafts. The caveolin proteins, through direct regulatory alescence. Nonetheless, taken together, these findings confirm interactions with other proteins (e.g., TLR4) (8), are in par- that membrane lipid remodeling is sufficient to drive cell sig- ticular thought to play a central role in signal regulation naling by reorganizing protein cargo, and they also demon- within caveolae. Of interest, although caveolae are well strate, perhaps paradoxically, that cholesterol depletion can studied in certain cell types (e.g., endothelial cells, fibroblasts) increase membrane order and coalescence of raft-like domains, and thought to be absent in others (e.g., lymphocytes), their a topic to which we return below. presence in macrophages is less well defined and indeed con- Notably, Ab-mediated crosslinking of several GPI-linked troversial, varying by macrophage type (reviewed in Ref. 9). proteins can also coalesce/remodel rafts and induce signaling Although rafts and/or caveolae promote immune receptor by copatching proteins within rafts. Crosslinking of external signaling in several pathways by serving as platforms for dy- leaflet raft proteins induces copatching and activation of inner namic assembly of signaling complexes, in other cases, raft leaflet raft proteins such as H-ras (25), whereas crosslinking of localization suppresses signaling (e.g., TGF-b and epidermal GM1 can interestingly induce its copatching with TLR4 (26) growth factor receptors) (10–12). Moreover, in addition to and CD18 (27). As oligomeric cholesterol-binding cytolysins concentrating signaling proteins, the lipid microenvironment such as listeriolysin O both cluster CD14-rich rafts (28) and of rafts may itself alter protein function (13), in some cases activate TLR4 (29), it seems plausible that some TLR4 ago- Downloaded from shaping signaling much more selectively than as just a simple nists may activate this
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