Abstract
Integrin αDβ2 is the most recently identified member of the leukocyte, or β2, subfamily of integrin heterodimers. Its distribution and functions on human leukocytes have not been clearly defined and are controversial. We examined these issues and found that αDβ2 is prominently expressed by leukocytes in whole blood from healthy human subjects, including most polymorphonuclear leukocytes and monocytes. We also found that αDβ2 is displayed by leukocytes in the alveoli of uninjured and inflamed human lungs and by human monocyte-derived macrophages and dendritic cells, indicating broad myeloid expression. Using freshly-isolated human monocytes, we found that αDβ2 delivers outside-in signals to pathways that regulate cell spreading and gene expression. Screening expression analysis followed by validation of candidate transcripts demonstrated that engagement of αDβ2 induces mRNAs encoding inflammatory chemokines and cytokines and secretion of their protein products. Thus, αDβ2 is a major member of the integrin repertoire of both circulating and tissue myeloid leukocytes in humans. Its broad expression and capacity for outside-in signaling indicate that it is likely to have important functions in clinical syndromes of infection, inflammation, and tissue injury.
Highlights
Integrins are plasma membrane ab heterodimers that are broadly distributed on metazoan cells and that mediate critical functions including adhesion, homing, mechanical linkage of cytoskeletal elements to extracellular matrix, cell-cell interactions, ‘‘outside-in’’ signaling, and cell survival [1,2,3]
We examined the pattern of expression of aDb2 on human monocytes, since these leukocytes are critical immune effector cells and are precursors of macrophages and dendritic cells [40, 41]
We found that integrin aDb2 is highly expressed on unfractionated human monocytes when examined by flow cytometry after separation from other blood cells (Figure 1B)
Summary
Integrins are plasma membrane ab heterodimers that are broadly distributed on metazoan cells and that mediate critical functions including adhesion, homing, mechanical linkage of cytoskeletal elements to extracellular matrix, cell-cell interactions, ‘‘outside-in’’ signaling, and cell survival [1,2,3]. The leukocyte integrins have essential activities in physiologic and pathologic inflammatory and immune responses. Their requirement for host defense against invading pathogens is clearly demonstrated by heritable leukocyte adhesion deficiency syndromes in humans in which b2 integrin expression is dramatically reduced or absent, or intracellular mechanisms that control the adhesive functions of these integrins are disrupted [4,5,6,7,8]. In this study we examined these issues, focusing on myeloid leukocytes from human blood
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