Data from several investigators suggest that the ␣21 integrin, a receptor for collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1, endorepellin, and several viruses, is required for innate immunity and regulation of autoimmune/ allergic disorders. We demonstrated that the innate immune response to Listeria monocytogenes required ␣21 integrin expression by peritoneal mast cells (PMCs). Ligation of the ␣21 integrin by C1q contained in immune complexes comprised of Listeria and antibody was required for PMC activation in vitro and in vivo. However, ligation of the ␣21 integrin alone was insufficient to activate cytokine secretion, suggesting that one or more additional signals emanating from a coreceptor were required for PMC activation. Here, we demonstrate that C1q, but neither other complement proteins nor FcR␥, is required for early innate immune response to Listeria. IntroductionThe role of the ␣21 integrin in the innate and acquired immune response has been an area of active investigation. We initially reported that the ␣21 integrin-deficient mice exhibited markedly diminished inflammatory responses to Listeria monocytogenes because of a requirement for ␣21 integrin expression on peritoneal mast cells (PMCs) for mast-cell activation and cytokine release in vivo. 1 Although the ␣21 integrin serves as a receptor for several matrix and nonmatrix ligands, the ligand for the integrin during the PMC response to infection was unknown. 2,3 We demonstrated that C1q complement protein and collectin family members, including mannose binding lectin and surfactant protein A, all served as ligands for the integrin. 4 In addition, the ␣21 integrin was required for mast-cell activation in vitro in response to Listeria. However, ligation of the ␣21 integrin alone was insufficient to activate cytokine secretion because mast-cell adhesion to collagen or C1q alone failed to support cytokine secretion. 4 We hypothesized that one or more additional signals emanating from an additional receptor was required to activate mast-cell cytokine secretion in response to immune complexes. At that time, we presented 2 alternative models by which ␣21 integrin-ligand interactions may stimulate mast-cell activation and cytokine secretion. Our first model proposed that ligation of the ␣21 integrin simultaneously with a second, costimulatory receptor elicited mast-cell activation, in a manner reminiscent of the role proposed for the ␣21 integrin and the glycoprotein VI/Fc receptor common ␥ chain (FcR␥) during platelet adhesion to collagen. 5,6 In our second model, binding of the ␣21 integrin to an immune complex containing C1q may directly activate the complement cascade, resulting in the deposition of C3b or iC3b and generation of complement byproducts, such as C3a or C5a, which would subsequently stimulate mast cell activation. [7][8][9] We now report that neither the FcR␥ nor components of the complement cascade are required in ␣21 integrin-dependent mast-cell activation. Instead, we describe a novel coreceptor...
Integrins are alphabeta heterodimeric receptors that connect the extracellular environment with intracellular signaling events. Integrins are important for normal development and function, but are also involved in the pathogenesis of diseases including cancer, autoimmunity and heart disease. We will review the present data on a family of integrins, the collagen receptors that include the alpha1beta1, alpha2beta1, alpha1beta1 and alpha1beta1 integrins. We will describe the knowledge gained from genetic deletion of each integrin in animal models. Mice lacking any single collagen receptor display no overt defect. However, studies using the alpha1beta1 and alpha2beta1 integrin-deficient mice indicate that these receptors play an important role in innate immunity, inflammation and autoimmunity. Finally, we will elucidate the interesting and sometimes overlapping roles for alpha1beta1 and alpha2beta1 integrins in disease and will propose potential stategies to therapeutically target these receptors to alleviate or treat disease.
Mast cells, critical mediators of inflammation and anaphylaxis, are poised as one of the first lines of defense against external assault. Mast cells release several classes of preformed and de novo synthesized mediators. Cross-linking of the high-affinity FcΕRI results in degranulation and the release of preformed, proinflammatory mediators including histamine and serotonin. We previously demonstrated that mast cell activation by Listeria monocytogenes requires the α2β1 integrin for rapid IL-6 secretion both in vivo and in vitro. However, the mechanism of IL-6 release is unknown. Here, we demonstrate the Listeria- and α2β1 integrin-mediated mast cell release of preformed IL-6 without the concomitant release of histamine or β-hexosaminidase. α2β1 integrin-dependent mast cell activation and IL-6 release is calcium independent. In contrast, IgE cross-linking-mediated degranulation is calcium dependent and does not result in IL-6 release, demonstrating that distinct stimuli result in the release of specific mediator pools. These studies demonstrate that IL-6 is presynthesized and stored in connective tissue mast cells and can be released from mast cells in response to distinct, α2β1 integrin-dependent stimulation, providing the host with a specific innate immune response without stimulating an allergic reaction.
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