Mast cell–mediated inflammatory responses require the α2β1 integrin

Abstract

Although the ␣2␤1 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 ␣2␤1 integrin, it seemed unlikely that this integrin mediated neutrophil migration directly. Here, we demonstrate constitutive ␣2␤1 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 ␣2␤1 integrin provides a costimulatory function required for mast cell activation and cytokine production in response to infection. IntroductionThe ␣2␤1 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 ␣2␤1 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 ␣2␤1 integrin), and on neutrophils (polymorphonuclear leukocytes [PMNs]). 2,3 Although the role of the ␣2␤1 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 ␣2␤1 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 ␣2␤1 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 ␣2␤1 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 ␣2␤1 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-...

Mast Cell Cathelicidin Antimicrobial Peptide Prevents Invasive Group A Streptococcus Infection of the Skin

“…In our model, mice reconstituted with Camp ϩ/ϩ cells inhibited edema to a higher extent than the mice reconstituted with Camp Ϫ/Ϫ MC, indicating that cathelicidin might have a modulating effect on the antiinflammatory cytokine production. Moreover, we were able to confirm previous observations that MC are able to modulate neutrophilic infiltration (8,11,51). This effect may be partially modified by the presence of cathelicidin inside MC.…”

TLR3-, TLR7-, and TLR9-Mediated Production of Proinflammatory Cytokines and Chemokines from Murine Connective Tissue Type Skin-Derived Mast Cells but Not from Bone Marrow-Derived Mast Cells

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Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss

“…The reduced levels of RANKL and osteoclast numbers by a2b1 integrin mAb in IL-7-treated mice can be attributed at least to the reduction of IL-17 levels because IL-17 is a strong inducer of RANKL in stromal cells and osteoblasts (4, 5, 44). Although IL-7/IL-7R signaling has recently been involved in myeloid cells of RA (18), it is unlikely that the blockade of IL-7-induced bone loss by anti-a2b1 mAb occurs at the level of myeloid cells because a2b1 integrin expression is not associated with neutrophils or monocytic/macrophage lineage (45)(46)(47), which constitutes the main source of osteoclast precursors. In addition, previous studies and recent evidence from the a2b1 integrindeficient mice indicated that although osteoclasts may express a2b1 integrin, it seems that their function depends more on avb3 integrin rather than on a2b1 and other integrins (48,49).…”