Crosstalk between the α2β1 integrin and c-met/HGF-R regulates innate immunity

Abstract

Data from several investigators suggest that the ␣2␤1 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 ␣2␤1 integrin expression by peritoneal mast cells (PMCs). Ligation of the ␣2␤1 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 ␣2␤1 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 ␣2␤1 integrin in the innate and acquired immune response has been an area of active investigation. We initially reported that the ␣2␤1 integrin-deficient mice exhibited markedly diminished inflammatory responses to Listeria monocytogenes because of a requirement for ␣2␤1 integrin expression on peritoneal mast cells (PMCs) for mast-cell activation and cytokine release in vivo. 1 Although the ␣2␤1 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 ␣2␤1 integrin was required for mast-cell activation in vitro in response to Listeria. However, ligation of the ␣2␤1 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 ␣2␤1 integrin-ligand interactions may stimulate mast-cell activation and cytokine secretion. Our first model proposed that ligation of the ␣2␤1 integrin simultaneously with a second, costimulatory receptor elicited mast-cell activation, in a manner reminiscent of the role proposed for the ␣2␤1 integrin and the glycoprotein VI/Fc receptor common ␥ chain (FcR␥) during platelet adhesion to collagen. 5,6 In our second model, binding of the ␣2␤1 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 ␣2␤1 integrin-dependent mast-cell activation. Instead, we describe a novel coreceptor...

β1 integrin is a crucial regulator of pancreatic β-cell expansion

“…The signaling properties of integrin receptors are dictated primarily by their state of activation resulting from ECM ligand occupancy and/or cis-transactivation through interaction with 3367 RESEARCH ARTICLE Integrins in islet development growth factor receptors harboring tyrosine kinase functions, rather than by their levels of expression (Fujita et al, 2013;Giancotti and Ruoslahti, 1999;Ju and Zhou, 2013;Liddington and Ginsberg, 2002;Margadant et al, 2011;McCall-Culbreath et al, 2008;Mitra et al, 2011;Wang et al, 1998). Nevertheless, it is reasonable to infer that the levels of β1 integrin expression detected in different pancreatic epithelial cell types correlate with cell type-specific proliferative capabilities.…”

An Alternative Role of C1q in Cell Migration and Tissue Remodeling: Contribution to Trophoblast Invasion and Placental Development

“…Similar results were obtained by Feng and colleagues (46), who showed that EC adhesion and spreading on C1q-coated microtiter wells was prevented both by mAb 60.11 to gC1qR and mAb to b 1 integrins and that gC1qR and b 1 integrin cocaptured on C1q-bound ECs. Involvement of integrins in cell activation by C1q has also been established on murine mast cells that have been shown to express a 2 b 1 integrin as a novel receptor for the collagen-like sequence of C1q (64)(65)(66).…”

The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

“…Moreover, in mice gene targeting of the MET signaling pathway, through deletion of the gene encoding plasminogen activator, urokinase receptor (Plaur), which controls levels of HGF, results in reduced numbers of neocortical interneurons, spontaneous seizures (which occur in 20%-30% of children with ASD), increased anxiety, and reduced social interactions (76)(77)(78). Additionally, MET signaling participates in autonomic nervous system and cerebellar development, immune function, and gastrointestinal function and repair (79)(80)(81)(82)(83)(84). Disruptions of these neural and peripheral elements have been reported in ASD (85)(86)(87)(88)(89)(90).…”