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Apoptotic Cells by Camp Regulation of Macrophage Phagocytosis Of Regulation of Macrophage Phagocytosis of Apoptotic Cells by cAMP Adriano G. Rossi, Judith C. McCutcheon, Noémi Roy, Edwin R. Chilvers, Christopher Haslett and Ian Dransfield This information is current as of September 29, 2021. J Immunol 1998; 160:3562-3568; ; http://www.jimmunol.org/content/160/7/3562 References This article cites 32 articles, 19 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/160/7/3562.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 Subscription Information about subscribing to The Journal of Immunology is online at: by guest on September 29, 2021 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Regulation of Macrophage Phagocytosis of Apoptotic Cells by cAMP1 Adriano G. Rossi,2 Judith C. McCutcheon, Noe´mi Roy, Edwin R. Chilvers, Christopher Haslett, and Ian Dransfield Regulation of macrophage capacity to remove apoptotic cells may control the balance of apoptotic and necrotic leukocytes at inflamed foci and the extent of leukocyte-mediated tissue damage. Although the molecules involved in the phagocytic process are beginning to be defined, little is known about the underlying regulatory and signaling mechanisms controlling this process. In this paper, we have investigated the effects of treatment of human monocyte-derived macrophages with PGs and other agents that elevate intracellular cAMP on phagocytosis. PGE2 and PGD2 specifically reduced the proportion of macrophages that phagocy- tosed apoptotic cells. Similar results were obtained with the membrane-permeable cAMP analogues dibutyryl-cAMP and 8-bro- Downloaded from mo-cAMP but not with the cGMP analogue dibutyryl-GMP. Consistent with the observation that phagocytosis was inhibited by cAMP elevation, treatment of monocyte-derived macrophages with PGE2 resulted in rapid, transient increase in levels of intra- cellular cAMP. These effects were not due to nonspecific inhibition of monocyte-derived macrophage phagocytosis given that ingestion of Ig-opsonized erythrocytes was unaffected. Elevation of cAMP induced morphologic alterations indicative of changes in the adhesive status of the macrophage, including cell rounding and disassembly of structures that represent points of contact with substrate containing actin and talin. These results strongly suggest that rapid activation of cAMP signaling pathways by http://www.jimmunol.org/ inflammatory mediators regulates processes that limit tissue injury and that modulation of cAMP levels represents an additional therapeutic target in the control of resolution of inflammation. The Journal of Immunology, 1998, 160: 3562–3568. he ultimate fate of the large numbers of recruited neutro- neutrophils are observed at chronically inflamed sites; thus, the phil granulocytes during inflammatory responses has been tissue load of apoptotic cells is likely to be a critical factor in T widely assumed to involve necrosis and disintegration in determining the outcome of inflammation. situ before cellular fragments are cleared by local phagocytes (1). Potential control mechanisms for regulation of the recognition However, the capacity of many granule contents to cause cellular and phagocytic pathways by which apoptotic cells are removed injury (2) and cleave tissue matrix proteins into chemotactic frag- include prolongation of myeloid cell functional longevity, such as by guest on September 29, 2021 ments (3) implies that necrotic cell death would damage healthy phagocytic and secretory responses by inflammatory mediators tissues and exacerbate inflammatory processes. There is now com- and growth factors (10–12). Inhibition of the rate of apoptosis in pelling evidence that neutrophil apoptosis, which is associated these cell populations at inflamed sites would serve a dual purpose with preservation of granule contents and down-regulation of ef- of regulating the potential for neutrophil-mediated damage at these fector function, including granule secretion (4, 5), limits the po- sites and the numbers of neutrophils that are available for recog- tential for neutrophil-mediated tissue damage during progression nition by macrophages. Inflammatory mediators also act to regu- of inflammatory responses (reviewed in Ref. 6). An important late phagocytosis of apoptotic cells by macrophages. Multiple re- consequence of the apoptotic process is cell surface alterations ceptor pathways are implicated in the phagocytosis of apoptotic that lead to rapid recognition and phagocytosis of apoptotic cells, although specific pathways may be dominant in certain en- neutrophils (4, 7). In contrast to macrophage phagocytosis of vironmental conditions (13, 14). For human monocyte-derived particles opsonized with C or Ig, this does not provoke the macrophages, we have proposed a model in which macrophage release of proinflammatory macrophage mediators (thrombox- a b v 3 and CD36 act in concert to allow apoptotic cell recognition ane B or N-acetyl-b-D-glucosaminidase) (8), contributing to 2 (7, 13). Modulation of receptor expression during monocyte dif- limitation of tissue injury and promotion of resolution of in- ferentiation may determine the phagocytic ability of macrophage flammation. There is clear histologic evidence for the involve- populations at different anatomic sites. Induction of a b occurs ment of this process in acute inflammation (9), and necrotic v 3 concomitantly with the acquisition of the capacity to phagocytose apoptotic cells during in vitro culture of monocytes (15). For mu- Respiratory Medicine Unit, Department of Medicine (RIE), Rayne Laboratory, The rine macrophages, different phenotypes may be induced by local University of Edinburgh Medical School, Edinburgh, U.K. microenvironmental stimuli. Bone marrow-derived macrophages, Received for publication August 15, 1997. Accepted for publication December in contrast to those isolated from the peritoneal cavity which uti- 9, 1997. a b lize a phosphatidylserine based pathway, use an v 3 integrin- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance based recognition mechanism (16). In addition, phagocytosis of with 18 U.S.C. Section 1734 solely to indicate this fact. b-1,3-glucan particles can induce a switch between these two path- 1 This work was supported by the Medical Research Council, U.K., and the Faculty ways (17). There is also clear evidence that macrophage phago- of Medicine at the University of Edinburgh. cytic responses are also influenced by integrin-mediated signal 2 Address correspondence and reprint requests to Dr. Adriano G. Rossi, Respiratory transduction pathways (18). Thus, control of apoptotic cell re- Medicine Unit, Department of Medicine (RIE), Rayne Laboratory, The University of Edinburgh Medical School, Teviot Place, Edinburgh, EH8 9AG Scotland, U.K. moval may be achieved by regulation of macrophage phagocytic E-mail address: [email protected] potential. Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 The Journal of Immunology 3563 In this study, we have investigated whether modulation of of phagocytic macrophages of triplicate wells or as the percentage phago- protein kinase activity had a regulatory role in the process of mac- cytosis relative to untreated controls. rophage recognition of apoptotic cells. In particular, we have ex- Macrophage phagocytosis of IgG-opsonized erythrocytes amined the effects of short term treatment of human monocyte- Erythrocytes were washed and resuspended at 2.5 3 107/ml in Iscove’s derived macrophages with PGs, which elevate intracellular cAMP. DMEM and incubated at 4°C with rabbit polyclonal anti-human erythro- Our results suggest that specific inhibition of phagocytosis of ap- cyte Ab (1:100) for 30 min. Opsonized erythrocytes were then washed and optotic neutrophils following cAMP elevation may involve disas- resuspended at 1 3 106/ml in Iscove’s DMEM and incubated with mac- sembly of cytoskeletal elements involved in cell-substratum inter- rophages at a macrophage-erythrocyte ratio of 1:2. action without inducing cell detachment. These data support a Flow cytometry and immunocytochemistry model in which the matrix microenvironment exerts control over Flow cytometry was performed as described previously (19, 20), with all the macrophage capacity for clearance of apoptotic cells. Thus, incubations conducted on ice. Six-day-old monocyte-derived macrophages pharmacologic targeting of elements of the PKA pathway may were detached from cell culture plates by vigorous pipetting after incuba- represent a novel strategy for the modulation of macrophage ca- tion on ice with PBS for 30 min. Macrophages (1 3 105) were washed with pacity for the clearance of apoptotic cells. ice-cold PBS containing 0.2% (w/v) BSA and 0.1% (w/v) sodium azide and preincubated with
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