Crucial Role of Phospholipase Cε in Induction of Local Skin Inflammatory Reactions in the Elicitation Stage of Allergic Contact Hypersensitivity

Hu, Lizhi; Edamatsu, Hironori; Takenaka, Nobuyuki; Ikuta, Shuzo; Kataoka, Tohru

doi:10.4049/jimmunol.0901816

Cited by 43 publications

(41 citation statements)

References 43 publications

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“…Whether mutations in PLCe1 are directly responsible for this clinical syndrome remains unclear. The role of PLCe1 in skin inflammation has been questioned before; however, it was suggested that the effects of this enzyme were not mediated exclusively by CD4 + cells and the involvement of other cell types, such as of fibroblasts and keratinocytes, has been suggested (29). Our work is not free of limitations.…”

Section: Discussionmentioning

confidence: 78%

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

Strazza

Azoulay-Alfaguter

Peled

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Ce 1 (PLCe1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCe1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structurefunction experiments to separate the dual-enzymatic function of PLCe1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCe1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCe1, suggesting that PLCe1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.

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Section: Discussionmentioning

confidence: 78%

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

Strazza

Azoulay-Alfaguter

Peled

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Section: Kato Et Al Epac1 Deficiency Attenuated Neointimal Formation mentioning

confidence: 99%

“…Recent studies suggest that PLCε cooperates with nuclear factor-κB to induce proinflammatory-related mediators, such as CXCL2 and cyclooxygenase 2, which are upregulated at the vascular injury site. [47][48][49] In addition to the potential role of PLCε in Epac1-mediated migration, further studies on the roles of PLCε as a downstream signaling effector of PDGF-BB-Epac are required.As mentioned above, Rap1 contributes to Epac1-mediated cell migration in various cell types. 11,27,31,34,50 However, a subtype-specific differential effect of Rap1 on cell migration has been reported.…”

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confidence: 99%

Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation

Kato

Yokoyama

Yanai

et al. 2015

ATVB

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Consistent with this evidence, exogenously administered PDGF-BB into the rat carotid artery after endothelial denudation increased neointimal lesions. 2,4 In addition, genetic deletion of PDGFR-β decreased SMC accumulation in atherosclerotic lesions. 2,5 This accumulating evidence suggests that PDGF-BB and PDGFR-β signaling play a prominent role in vascular SMC migration into the neointima after vascular injury and during the development of atherosclerosis. 2It has been suggested that PDGF-BB-mediated cell migration is attributed to the activation of intracellular signal transduction pathways, including phosphatidylinositol 3-kinase, mitogen-activated protein kinase cascade, and © 2015 American Heart Association, Inc. Objective-Vascular smooth muscle cell (SMC) migration causes neointima, which is related to vascular remodeling after mechanical injury and atherosclerosis development. We previously reported that an exchange protein activated by cAMP (Epac) 1 was upregulated in mouse arterial neointima and promoted SMC migration. In this study, we examined the molecular mechanisms of Epac1-induced SMC migration and the effect of Epac1 deficiency on vascular remodeling in vivo. Approach and Results-Platelet-derived growth factor-BB promoted a 2-fold increase in SMC migration in a primary culture of aortic SMCs obtained from Epac1 +/+ mice (Epac1 +/+ -ASMCs), whereas there was only a 1.2-fold increase in Epac1 −/− -ASMCs. The degree of platelet-derived growth factor-BB-induced increase in intracellular Ca 2+ was smaller in Fura2-labeled Epac1 −/− -ASMCs than in Epac1 +/+ -ASMCs. In Epac1 +/+ -ASMCs, an Epac-selective cAMP analog or platelet-derived growth factor-BB increased lamellipodia accompanied by cofilin dephosphorylation, which is induced by Ca 2+ signaling, whereas these effects were rarely observed in Epac1−/− -ASMCs. Furthermore, 4 weeks after femoral artery injury, prominent neointima were formed in Epac1 +/+ mice, whereas neointima formation was significantly attenuated in Epac1 −/− mice in which dephosphorylation of cofilin was inhibited. The chimeric mice generated by bone marrow cell transplantation from Epac1 +/+ into Epac1 −/− mice and vice versa demonstrated that the genetic background of vascular tissues, including SMCs rather than of bone marrow-derived cells affected Epac1-mediated neointima formation. Conclusions-These data suggest that Epac1 deficiency attenuates neointima formation through, at least in part, inhibition of SMC migration, in which a decrease in Ca 2+ influx and a suppression of cofilin-mediated lamellipodia formation occur. 6,7 In addition to these signaling pathways, it has been recognized that PDGF-BB increases intracellular cAMP via a G protein-coupled receptor transactivation mechanism. 8,9 However, the role of PDGF-BB-induced cAMP in SMC migration remains unknown.A major second messenger cAMP activates protein kinase A (PKA) and an exchange protein activated by cAMP (Epac). 10Epac has 2 isoforms, Epac1 and Epac2, both of which are activated in living cells by physiol...

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“…Primary cultures of epidermal keratinocytes and dermal fibroblasts were performed as described previously 30 with minor modifications. Briefly, epidermal keratinocytes were isolated from the dorsal skin of newborn mice at postnatal day 1 and seeded with defined keratinocyte-SFM supplemented with growth factors onto plastic plates coated with type 1-A collagen (Nitta gelatin, Osaka, Japan).…”

Section: Primary Cultures Of Epidermal Keratinocytes and Dermal Fibromentioning

confidence: 99%

Phospholipase Cɛ has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC

Oka

Edamatsu

Kunisada

et al. 2011

Laboratory Investigation

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Phospholipase C (PLC) e is a phosphoinositide-specific PLC regulated by small GTPases including Ras and Rap. We previously demonstrated that PLCe has an important role in the development of phorbol ester-induced skin inflammation. In this study, we investigated the role of PLCe in ultraviolet (UV) B-induced acute inflammatory reactions in the skin. Wild-type (PLCe þ / þ ) and PLCe gene knockout (PLCe À/À ) mice were irradiated with a single dose of UVB at 1, 2.5, and 10 kJ/m 2 on the dorsal area of the skin, and inflammatory reactions in the skin were histologically evaluated up to 168 h after irradiation. In PLCe þ / þ mice, irradiation with 1 and 2.5 kJ/m 2 UVB resulted in dose-dependent neutrophil infiltration in the epidermis at 24 and 48 h after irradiation. When mice were irradiated with 10 kJ/m 2 of UVB, most mice developed skin ulcers by 48 h and these ulcers became more severe at 168 h. In PLCe À/À mice, UVB (1 or 2.5 kJ/m 2 )-induced neutrophil infiltration was markedly suppressed compared with PLCe þ / þ mice. The suppression of neutrophil infiltration in PLCe À/À mice was accompanied by attenuation of UVB-induced production of CXCL1/keratinocyte-derived chemokine (KC), a potent chemokine for neutrophils, in the whole skin. Cultured epidermal keratinocytes and dermal fibroblasts produced CXCL1/KC in a PLCe-dependent manner after UVB irradiation, and the UVB-induced upregulation of CXCL1/KC in these cells was significantly abolished by a PLC inhibitor. Furthermore, UVB-induced epidermal thickening was noticeably reduced in the skin of PLCe À/À mice. These results indicate that PLCe has a crucial role in UVB-induced acute inflammatory reactions such as neutrophil infiltration and epidermal thickening by at least in part regulating the expression of CXCL1/KC in skin cells such as keratinocytes and fibroblasts.

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Crucial Role of Phospholipase Cε in Induction of Local Skin Inflammatory Reactions in the Elicitation Stage of Allergic Contact Hypersensitivity

Cited by 43 publications

References 43 publications

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation

Phospholipase Cɛ has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC

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