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Dβ2 Is Dynamically Expressed by Inflamed Macrophages and Alters the Natural History of Lethal Systemic Infections1
,
,
,
* Program in Human Molecular Biology and Genetics,
Huntsman Cancer Institute,
Department of Internal Medicine, and
Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
¶ Laboratório de Immunofarmacologia, Departmento de Fisiologia e Farmacodinamica, Instituto Oswaldo Cruz, Fundacão Oswaldo Cruz, Rio de Janeiro, Brazil
The leukocyte integrins have critical roles in host defense and inflammatory tissue injury. We found that integrin 
Dβ2, a novel but largely uncharacterized member of this family, is restricted to subsets of macrophages and a small population of circulating leukocytes in wild-type mice in the absence of inflammatory challenge and is expressed in regulated fashion during cytokine-induced macrophage differentiation in vitro. Dβ2 is highly displayed on splenic red pulp macrophages and mediates their adhesion to local targets, identifying key functional activity. In response to challenge with Plasmodium berghei, a malarial pathogen that models systemic infection and inflammatory injury, new populations of D+ macrophages evolved in the spleen and liver. Unexpectedly, targeted deletion of D conferred a survival advantage in P. berghei infection over a 30-day observation period. Mechanistic studies demonstrated that the increased survival of D–/– animals at these time points is not attributed to differences in magnitude of anemia or parasitemia or to alterations in splenic microanatomy, each of which is a key variable in the natural history of P. berghei infection, and indicated that an altered pattern of inflammatory cytokines may contribute to the difference in mortality. In contrast to the outcome in malarial challenge, death of D–/– animals was accelerated in a model of Salmonella sepsis, demonstrating differential rather than stereotyped roles for Dβ2 in systemic infection. These studies identify previously unrecognized and unique activities of Dβ2, and macrophages that express it, in host defense and injury.
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 with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant HL44525 (to G.A.Z.), a National Institutes of Health Special Center of Research in Acute Respiratory Distress Syndrome (P50 H150153), an Asthma Research Center Award funded by the American Lung Association, the Margolis Foundation, and an Established Investigator Award from the American Heart Association (to A.S.W.).
2 Y.M. and M.B. contributed equally to this work. M.B. accomplished cloning of the mouse D gene, generation of D-deficient animals, initial genotype-phenotype correlation, and development of in vitro models of D expression. Y.M. performed extensive characterization of Dβ2 in murine tissues and additional genotype-phenotype correlation, developed in vitro models of cellular adhesion, characterized D expression in in vivo disease models, and compiled major portions of the manuscript text.
3 Current address: Department of Integrated Pulmonology Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, Japan, 233-0015.
4 Current address: Invitrogen Corporation, 1610 Faraday Avenue, Carlsbad, CA 92008.
5 Current address: Department of Cell Biology, NN1-28, Lerner Research Institute, Cleveland, OH 44195.
6 Current address: Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104.
7 Address correspondence and reprint requests to Dr. Guy A. Zimmerman, Program in Human Molecular Biology and Genetics, University of Utah, 15 North 2030 East, Building 533, Room 4220, Salt Lake City, UT 84112. E-mail address: guy.zimmerman{at}hmbg.utah.edu
8 Abbreviations used in this paper: WT, wild type; PRBC, parasitized RBC; iNOS, inducible NO synthase.
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