Although the ␣21 integrin is widely expressed and has been extensively studied, it has not been previously implicated in mast cell biology. We observed that ␣2 integrin subunit-deficient mice exhibited markedly diminished neutrophil and interleukin-6 responses during Listeria monocytogenes-and zymosan-induced peritonitis. Since exudative neutrophils of wildtype mice expressed little ␣21 integrin, it seemed unlikely that this integrin mediated neutrophil migration directly. Here, we demonstrate constitutive ␣21 integrin expression on peritoneal mast cells. Although ␣2-null mice contain normal numbers of peritoneal mast cells, these ␣2-null cells do not support in vivo mast cell-dependent inflammatory responses.We conclude that ␣21 integrin provides a costimulatory function required for mast cell activation and cytokine production in response to infection.
IntroductionThe ␣21 integrin, a receptor for collagen, laminin, and other nonmatrix ligands, is expressed on a number of distinct cell types including epithelial cells, endothelial cells, fibroblasts, platelets, and leukocytes. 1 On cells of the immune system, the ␣21 integrin is expressed on a subset of activated T lymphocytes (hence the designation very late activation antigen-2), on natural killer (NK) cells (DX5, originally defined as an NK cell-specific marker, was recently shown to recognize the ␣21 integrin), and on neutrophils (polymorphonuclear leukocytes [PMNs]). 2,3 Although the role of the ␣21 integrin in immune regulation is poorly understood, accumulating evidence suggests that this integrin may play an important role in leukocyte adhesion and extravasation from the vasculature into peripheral tissues. [4][5][6] Recently, we generated an ␣2 integrin subunit-deficient mouse model to investigate the role of the ␣21 integrin in normal development and the pathogenesis of disease. 7 Here, we report that the ␣2 integrin-deficient mouse demonstrates a profound and surprising defect in the innate immune response during acute peritonitis. ␣2 integrin-deficient mice exhibit markedly diminished inflammatory responses to both Listeria monocytogenes, a gram-positive bacterium, and zymosan, a fungal polysaccharide. Although the PMNs of the ␣2 integrin-deficient mouse lack expression of this integrin, the inflammatory defect in these mice is not due to an inability of the PMNs to extravasate into the peritoneum. Instead, the ␣21 integrin is expressed at high levels on all peritoneal mast cells (PMCs), a cell type required for the induction of the inflammatory response to infection. 8,9 We demonstrate that ␣21 integrin expression on the PMC is required for mast cell activation and cytokine release in response to a number of agents in vivo and that ␣21 integrin expression on the PMC is necessary for induction of normal inflammatory responses.
Materials and methods
Mice␣2 integrin-deficient mice on a C57BL/6 ϫ 129/Sv background were used at 6 to 20 weeks of age, with wild-type littermate controls. 7 Mice were maintained and bred under specific pathogen-...