Integrin αDβ2 Is Dynamically Expressed by Inflamed Macrophages and Alters the Natural History of Lethal Systemic Infections

Abstract

The leukocyte integrins have critical roles in host defense and inflammatory tissue injury. We found that integrin αDβ2, 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. αDβ2 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 αD+ macrophages evolved in the spleen and liver. Unexpectedly, targeted deletion of αD conferred a survival advantage in P. berghei infection over a 30-day observation period. Mechanistic studies demonstrated that the increased survival of αD−/− 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 αD−/− animals was accelerated in a model of Salmonella sepsis, demonstrating differential rather than stereotyped roles for αDβ2 in systemic infection. These studies identify previously unrecognized and unique activities of αDβ2, and macrophages that express it, in host defense and injury.

Integrin αDβ2 (CD11d/CD18) Is Expressed by Human Circulating and Tissue Myeloid Leukocytes and Mediates Inflammatory Signaling

“…Integrin α D β 2 mediates adhesion of murine and human leukocytes and cell lines in vitro [14],[24],[25],[30], consistent with adhesive activities of β 2 integrins that contribute to leukocyte targeting and localization [1]–[5],[8]. Integrins, including leukocyte integrins, also transmit “outside-in” signals that are linked to key intracellular transduction cascades [1],[4],[48],[49].…”

“…Indirect experiments by other investigators suggest that α D β 2 also potentiates the release of interferon gamma by human natural killer cells [21],[22]. Consistent with these observations, targeted deletion of α D in mice – resulting in absence of α D β 2 – yielded changes in cytokine and chemokine profiles in experimental models of malaria and Salmonella infection ([14]; manuscript submitted). The latter experiments suggest that outside-in signaling resulting from engagement of α D β 2 regulates inflammatory chemokine and cytokine synthesis in vivo , as well as in vitro .…”

The Upregulation of Integrin αDβ2 (CD11d/CD18) on Inflammatory Macrophages Promotes Macrophage Retention in Vascular Lesions and Development of Atherosclerosis

“…It has been shown that anti-CD11d antibody reduced the inflammation (5–7) and macrophage accumulation (42,43) after spinal cord injury and CD11d-deficiency has a protective effect during P. berghei malaria infection (9). In contrast, the survival of CD11d −/− mice after Salmonella typhimurium sepsis was reduced (8). Despite different outcomes, these results demonstrate that CD11d alters the systemic inflammatory response during acute inflammation.…”

“…Surprisingly, in comparison to other β 2 integrins, there is limited information on the function of CD11d/CD18. There are only a few publications that demonstrate the effect of CD11d on the development of the inflammatory response, and these have been studied in models of spinal cord injury (5–7), lethal systemic infections (8) and malaria (9). However, the molecular mechanism of CD11d function is still not understood.…”

Leukocyte β7 Integrin Targeted by Krüppel-like Factors

“…This feature appears to be a shared trait among KLFs because a similar regulatory loop was described for KLF4 (GKLF) (69). KLF4 also has been implicated in the regulation of integrins, because among myeloid cells KLF4 represses CD11d expression (70), an integrin (a D ) specifically expressed by red pulp macrophages (71). Thus, many evidences point to a general involvement of KLFs in the positioning of lymphocytes, particularly by regulating integrin expression.…”