Effect of laminin-332 pemphigoid IgG on the keratinocyte transcriptome
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PROVIDER: PRJNA757276 | ENA |
REPOSITORIES: ENA
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Project description:To determine the role of laminin-332 autoantibodies in inducing a pro-inflammatory and proteolytic response by keratinocytes
2021-08-26 | GSE182644 | GEO
Project description:Intravenous immunoglobulin (IVIg) is used to treat mucous membrane pemphigoid (MMP), although its therapeutic effectivity is not sufficiently supported by randomized controlled clinical trials and its mode of action is only insufficiently understood. We have examined the effect of IVIg in a mouse model of anti-laminin 332 MMP and found that IVIg ameliorates both cutaneous and mucosal inflammatory lesions. Our investigation into the modes of action of IVIg in MMP indicated effective antiinflammatory mechanisms beyond the enhanced degradation of IgG mediated through inhibition of the neonatal Fc receptor. Our results suggest that IVIg curbs the activation of neutrophils at several levels. This includes a direct, immediate inhibitory effect on neutrophil activation by immune complexes but not C5a which blunts the release of reactive oxygen species and leukotriene B4 from neutrophils. IVIg also suppresses the formation of neutrophil extracellular traps in response to Ca2+ ionophore. In vivo treatment with IVIg altered the transcriptome of blood leukocytes and bone marrow neutrophils towards less proinflammatory phenotypes. Collectively, our results support the effectivity of IVIg in the treatment of MMP and indicate that effects on neutrophils at multiple levels may significantly contribute to its therapeutic effects.
2024-04-10 | GSE263026 | GEO
Project description:Laminin-332 (Lm332; formerly laminin-5) is a basement membrane protein in the skin, which promotes cell motility in wound healing and cancer invasion. In a previous study, we reported that the introduction of bisecting GlcNAc into Lm332 (GnT-III-Lm332), catalyzed by N-acetylglucosaminyltransferase III (GnT-III), reduced cell migration (Kariya, Y., Kato, R., Itoh, S., Fukuda, T., Shibukawa, Y., Sanzen, N., Sekiguchi, K., Wada, Y., Kawasaki, N., and Gu, J. (2008) J. Biol. Chem. 283, 33036-33045). However, the underlying molecular mechanism by which GnT-III-Lm332 suppresses the normal biological functions of Lm332 remains to be elucidated. In this study, we show that galectin-3, which is a beta-galactoside-binding protein, strongly bound to unmodified Lm332 but not to GnT-III-Lm332 and that binding of galectin-3 was completely blocked by lactose. Exogenous galectin-3 significantly enhanced keratinocyte cell motility on control Lm332 but not on GnT-III-Lm332. A functional blocking antibody against galectin-3 inhibited Lm332-induced alpha3beta1 and alpha6beta4 integrin clustering and focal contact formation. Co-immunoprecipitation revealed that galectin-3 associated with both beta4 integrin and epidermal growth factor receptor, thereby cross-linking the two molecules. The associations were inhibited by either the presence of lactose or expression of GnT-III. Moreover, galectin-3 consistently enhanced ERK activation. Taken together, the results of this study are the first to clearly identify the molecular mechanism responsible for the inhibitory effects of GnT-III on extracellular matrix-integrin-meditated cell adhesion, migration, and signal transduction. The findings presented herein shed light on the importance of N-glycosylation-mediated supramolecular complex formation on the cell surface.
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Project description:RNA sequencing data of mouse epidermis isolated from wild type and LAMA3-deficient mice Genetic, clinical and biochemical studies concurred to establish that integrity of the dermal-epidermal junction requires laminin 332, a particular subset of epithelial laminins. Laminin 332 is composed of three subunits, α3, β3 and γ2, encoded by the Lama3, Lamb3 and Lamc2 genes, respectively. In vivo functional analysis of laminin 332 in skin has been prevented because constitutive mutations of any one of the coding genes, either inherited in human or engineered in mice, cause junctional epidermolysis bullosa and early death. Consequently, it is still unknown whether and how laminin 332 contributes to skin homeostasis. To circumvent the problem, we have generated a mouse model in which disruption of the Lama3 gene is conditional and specifically induced in epidermal keratinocytes after birth. It causes a progressive depletion of laminin 332 in the skin of the mouse, which is compatible with life. To assess how laminin 332 supervises epidermal homeostasis, RNA was prepared from keratinocytes isolated from laminin 332-depleted skin and control animals (three each) to compare their gene expression profiles using RNA sequencing.
2021-02-18 | GSE146045 | GEO
Project description:To elucidate the molecular mechanisms of tumor growth inhibition caused by the anti-LN-332 antibodies, we plated human A431 cells on plates coated with fibroblast-derived matrix for 6 hours and then added a mixture of antibodies against all three LN-332 chains or control IgG to the medium for 16 hours. All cells from antiobody treated and controls were collected and subjected to global transcriptome analysis using Affymetrix Human Genome U133 Plus 2.0 Arrays.
2008-06-14 | E-MEXP-1141 | biostudies-arrayexpress
Project description:Laminin 332, composed of the α3, β3 and γ2 chains, is an epithelial-basement membrane specific laminin variant. Its main role in normal tissues is the maintenance of epithelial-mesenchymal cohesion in tissues exposed to external forces, including skin and stratified squamous mucosa. After being secreted and deposited in the extracellular matrix, laminin 332 undergoes physiological maturation processes consisting in the proteolytic processing of domains located within the α3 and the γ2 chains. These maturation events are essential for laminin 332 integration into the basement membrane where it plays an important function in the nucleation and maintenance of anchoring structures. Studies in normal and pathological situations have revealed that laminin 332 can trigger distinct cellular events depending on the level of its proteolytic cleavages. In this review, the biological and structural characteristics of laminin 332 domains are presented and we discuss whether they trigger specific functions.
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Project description:Mammary epithelium is composed by luminal and basal epithelial cells, which are adhere to the basement membrane (BM). To dissect how basal cell functions are regulated by BM laminin adhesion, we performed RNA sequencing of basal human mammary epithelial cells adhered on laminin-111, -421 or -521 coated cell culture plates for 48 hours.
2022-11-07 | GSE197950 | GEO
Project description:Tulasnella sp. 332 Resequencing genome sequencing
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Project description:Gene-level analysis of gene expression in immortalized mouse keratinocyte lines that express or lack integrin alpha3beta1 The laminin-332-binding integrin alpha3beta1 is expressed highly in the epidermis, but its roles in regulating gene expression programs that promote normal or pathological skin remodeling have not been underexplored previously. In order to identify genes that are regulated by alpha3beta1 in keratinocytes, we used microarray approaches to identify alpha3beta1-dependent genes in mouse keratinocytes that were immortalized with SV40 large T antigen (i.e., MK cells).
2015-10-07 | GSE42041 | GEO
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