Integrin alphaDbeta2 is dynamically expressed by inflamed macrophages and alters the natural history of lethal systemic infections.
The leukocyte integrins have critical roles in host defense and inflammatory tissue injury. We found that integrin alphaDbeta2, 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. alphaDbeta2 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 alphaD+ macrophages evolved in the spleen and liver. Unexpectedly, targeted deletion of alphaD conferred a survival advantage in P. berghei infection over a 30-day observation period. Mechanistic studies demonstrated that the increased survival of alphaD-/- 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 alphaD-/- animals was accelerated in a model of Salmonella sepsis, demonstrating differential rather than stereotyped roles for alphaDbeta2 in systemic infection. These studies identify previously unrecognized and unique activities of alphaDbeta2, and macrophages that express it, in host defense and injury.
Miyazaki
Yasunari
Y
Program in Human Molecular Biology and Genetics, Huntsman Cancer Institute, Department of Internal Medicine, University of Utah, Salt Lake City 84112, USA.
Bunting
Michaeline
M
Stafforini
Diana M
DM
Harris
Estelle S
ES
McIntyre
Thomas M
TM
Prescott
Stephen M
SM
Frutuoso
Valber S
VS
Amendoeira
Fabio C
FC
de Oliveira Nascimento
Danielle
D
Vieira-de-Abreu
Adriana
A
Weyrich
Andrew S
AS
Castro-Faria-Neto
Hugo C
HC
Zimmerman
Guy A
GA
D000818:Animals; D018845:CD11 Antigens / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008288:Malaria / Q000276:immunology* / Q000401:mortality; D051379:Mice; D018345:Mice, Knockout; D010962:Plasmodium berghei; D012475:Salmonella; D018805:Sepsis / Q000276:immunology* / Q000401:mortality; D013154:Spleen / Q000276:immunology
D018845:CD11 Antigens; D016207:Cytokines; D039001:Integrin alpha Chains; C527123:integrin alphaD, mouse