Integrin Regulation during Leukocyte Recruitment Jan Herter and Alexander Zarbock This information is current as J Immunol 2013; 190:4451-4457; ; of September 24, 2021. doi: 10.4049/jimmunol.1203179 http://www.jimmunol.org/content/190/9/4451 Downloaded from References This article cites 76 articles, 40 of which you can access for free at: http://www.jimmunol.org/content/190/9/4451.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 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Integrin Regulation during Leukocyte Recruitment Jan Herter*,†,‡ and Alexander Zarbock*,† Integrins are recognized as vital players in leukocyte re- integrin activation: modulating the expression of signaling cruitment. Integrin malfunction causes severe disease receptors and ligands, curbing signaling pathways, and antag- patterns characterized by the inability to fight patho- onizing ligand binding of integrins. gens. Although inflammatory reactions are beneficial Although several details of the molecular mechanisms have and necessary for host defense, these reactions have to been unraveled, the current knowledge of the involved pathways be controlled to prevent tissue destruction and harmful is still fragmentary. Some parts, such as selectin-mediated slow sequelae. In this review, we discuss the different signaling leukocyte rolling and transmigration, are better understood than, pathways leading to the change of integrin adhesiveness for instance, G protein–coupled receptor (GPCR) signaling leading to integrin activation. Several in vitro findings, such as in neutrophils, monocytes, and lymphocytes. We thereby Downloaded from focus on the importance of integrin activation for the dif- rolling of monocytes at the site of inflammation, have yet to be ferent steps of the leukocyte recruitment cascade, in- confirmed under physiological conditions. Furthermore, the in- teraction among different integrins and their mutual activation cluding rolling, adhesion, postadhesion strengthening, during crawling and transmigration are still poorly defined. intravascular crawling, and transmigration, as each step Genetic mutation seen in patients with leukocyte adhesion necessitates the proper functioning of a distinct set of deficiency (LAD) syndromes provides a demonstration of the integrin molecules that has to be activated specifically. importance of these pathways: LAD-I is caused by mutations http://www.jimmunol.org/ Additionally, we discuss endogenous mechanisms that in the b2-integrin family that is predominantly involved in balance and counteract integrin activation and limit leukocyte/endothelial interactions (5). These patients present leukocyte recruitment at the site of inflammation. Fur- with recurrent infections, as leukocytes are unable to adhere ther insight into these complex mechanisms may provide and recruit to the site of inflammation. Patients with LAD-III new approaches for developing new anti-inflammatory additionally present with bleeding disorders. This mystery was therapies. The Journal of Immunology, 2013, 190: solved when the responsible mutations were found to affect 4451–4457. kindlin-3, a protein essential not only for b2-integrin acti- vation on leukocytes, but also for b3-integrin activation on by guest on September 24, 2021 recise targeting of leukocytes to their marked battle- platelets (5). grounds is a key strategy for victory by the immune Multiple animal studies have demonstrated promising clini- P defense (1). Although this complex process has been cal potential of therapeutic use of targeting integrin activation. a subject of intensive research for decades (2), many of the However, clinical trials have not shown the anticipated success. involved signaling pathways are still poorly understood (3). One reason for this observation could be the importance of Different sequential recruitment steps have been identified integrins in other key physiological systems (6). A better un- that each necessitates distinct functioning of particular derstanding of the involved molecular signaling pathways and members of the integrin family of adhesion molecules (1). physiological regulation mechanisms may unravel opportuni- These plasma membrane proteins feature a dual role of ties to tackle leukocyte recruitment and inflammation more sensing and interacting with the surrounding environment specifically and, ultimately, more successfully. (4). Even though various stimuli are known to activate in- tegrins in this context, the molecular details of the involved Integrin physiognomy signaling pathways are the subject of ongoing research. A Integrins are adhesion proteins affecting a wide variety of comparably new aspect is the idea of integrin regulation by cellular functions (7). Beyond their integral role in immune surrounding tissues at the site of inflammation. Recent pub- surveillance and leukocyte trafficking, integrins are critical lications identified physiological interceptions on all levels of players in development, hemostasis, and cancer and influence *Department of Anesthesiology, Intensive Care, and Pain Medicine, University of ing A1, University of Mu¨nster, 48149 Mu¨nster, Germany. E-mail address: zarbock@ Mu¨nster, 48149 Mu¨nster, Germany; †Max Planck Institute for Molecular Biomedi- uni-muenster.de cine, 48149 Mu¨nster, Germany; and ‡Center for Excellence in Vascular Biology, De- Abbreviations used in this article: ADAP, adhesion and degranulation–promoting adap- partment of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, tor protein; CalDAG-GEFI, Calcium diacylglycerol guanine nucleotide exchange factor Boston, MA 02115 I;Del-1,developmentalendotheliallocus-1;DHA,docosahexaenoicacid;GDF-15, Received for publication November 19, 2012. Accepted for publication February 17, growth differentiation factor-15; GEF, guanine nucleotide exchange factor; GPCR, G 2013. protein–coupled receptor; LAD, leukocyte adhesion deficiency; PLC, phospholipase C; PTX-3, pentraxin-3; SLP76, Src homology 2 domain–containing leukocyte phospho- This work was supported by German Research Foundation Grants AZ 428/3-1, AZ 428/ protein of 76 kDa; Syk, spleen tyrosine kinase. 6-1, SFB 1009/A5 (to A.Z.), and HE-6810/1-1 (to J.H.) and by a grant from the Interdisciplinary Center of Clinical Research (to A.Z.). Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 Address correspondence and reprint requests to Dr. Alexander Zarbock, Department of Anesthesiology, Intensive Care, and Pain Medicine, Albert Schweitzer Campus 1, Build- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1203179 4452 BRIEF REVIEWS: INTEGRIN REGULATION DURING LEUKOCYTE RECRUITMENT key cell cycle events (7). During inflammation, integrins are Furthermore, regulation of avidity is an important feature of linked to a diverse set of crucial processes that include an- integrin adhesiveness that has received increasing attention choring leukocytes to the extracellular matrix (inside–out sig- (13). However, the contribution of avidity to adhesiveness, its naling) and mediating signals in response to the surroundings investigation in vivo, and the cell’s active contribution to its either by binding of extracellular matrix proteins or ligands ex- regulation still pose a challenge for researchers, as changes of pressed on the surface of other cells (outside–in signaling) (4). avidity and affinity physiologically often go hand in hand To fulfill these duties, integrin assembly constitutes obligate (13). Formation of artificial clusters by crosslinking of in- noncovalently-bound heterodimers (8). At least 18 a- and 8 tegrins is commonly used to study outside–in signaling as it b-subunits have been identified in mammals, which generate evokes a strong stimulus into the cell (14). For LFA-1, high- 24 distinct integrins. However, several different splice variants resolution mapping of its surface distribution has revealed at are known, suggesting that the biological diversity of the least three different avidity patterns: randomly distributed integrin family is greater than currently recognized (7). The molecules, ligand-independent nanoclusters, and ligand- various leukocyte subsets in the circulation display different triggered macroclusters (15). Only preformed nanoclusters combinations of integrins. Neutrophils express predominantly can be dynamically recruited to the cell/cell interface to form b2-integrins, but also low amounts of b1- and b3-integrins. macroclusters (15). Monocytes express b1- and b2-integins, whereas lymphocytes Leukocyte recruitment possess a pattern of b1-, b2-, and b7-integrins varying with subtype and state of activation (9). We focus in this review on Leukocyte recruitment into inflamed tissue follows a well- Downloaded from b2-integrins