Rho and Anillin-dependent Control of mDia2 Localization and Function in Cytokinesis

Diaphanous-related formin, mDia, is an actin nucleation/polymerization factor functioning downstream of the small GTPase Rho. We found that, in addition to the Rho GTPase-mediated activation, the interaction between mDia2 and anillin is required for the localization and function of mDia2 in cytokinesis

LPA induces keratinocyte differentiation and promotes skin barrier function through the LPAR1/LPAR5-RHO-ROCK-SRF axis

ヒト表皮細胞の分化と皮膚バリア機能の調節機構を解明 --アトピー性皮膚炎の新たな治療戦略へ向けて--. 京都大学プレスリリース. 2018-11-16.The skin barrier protects our body from water loss, allergens and pathogens. Profilaggrin (proFLG) is produced by differentiated keratinocytes and is processed into FLG monomers. These monomers crosslink keratin filaments and are also decomposed to natural moisturizing factors in the stratum corneum for skin hydration and barrier function. Deficits in FLG expression impair skin barrier function and underlie skin diseases such as dry skin and atopic dermatitis (AD). However, intrinsic factors that regulate FLG expression and their mechanism of action remain unknown. Here, we show that lysophosphatidic acid (LPA) induces FLG expression in human keratinocytes via the LPAR1 and LPAR5 receptors and the downstream RHO-ROCK-SRF pathway. Comprehensive gene profiling analysis further revealed that LPA not only induces FLG expression but also facilitates keratinocyte differentiation. Moreover, LPA treatment significantly upregulated FLG production in a three-dimensional culture model of human skin, and promoted barrier function in mouse skin in vivo. Thus, our work demonstrates a previously unsuspected role for LPA and its downstream signaling in the maintenance of skin homeostasis, which may serve as a novel therapeutic target for skin barrier dysfunction

Aquaporin-3 potentiates allergic airway inflammation in ovalbumin-induced murine asthma

Oxidative stress plays a pivotal role in the pathogenesis of asthma. Aquaporin-3 (AQP3) is a small transmembrane water/glycerol channel that may facilitate the membrane uptake of hydrogen peroxide (H[2]O[2]). Here we report that AQP3 potentiates ovalbumin (OVA)-induced murine asthma by mediating both chemokine production from alveolar macrophages and T cell trafficking. AQP3 deficient (AQP3[-/-]) mice exhibited significantly reduced airway inflammation compared to wild-type mice. Adoptive transfer experiments showed reduced airway eosinophilic inflammation in mice receiving OVA-sensitized splenocytes from AQP3[-/-] mice compared with wild-type mice after OVA challenge, consistently with fewer CD4[+]T cells from AQP3[-/-] mice migrating to the lung than from wild-type mice. Additionally, in vivo and vitro experiments indicated that AQP3 induced the production of some chemokines such as CCL24 and CCL22 through regulating the amount of cellular H[2]O[2] in M2 polarized alveolar macrophages. These results imply a critical role of AQP3 in asthma, and AQP3 may be a novel therapeutic target

Clinical Relevance of Plasma Prostaglandin F_2α Metabolite Concentrations in Patients with Idiopathic Pulmonary Fibrosis

<div><p>Background</p><p>Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology with few current treatment options. Recently, we determined an important role of prostaglandin F_2α (PGF_2α) in pulmonary fibrosis by using a bleomycin-induced pulmonary fibrosis model and found an abundance of PGF_2α in bronchoalveolar lavage fluid of IPF patients. We investigated the role of PGF_2α in human IPF by assessing plasma concentrations of 15-keto-dihydro PGF_2α, a stable metabolite of PGF_2α.</p><p>Methods</p><p>We measured plasma concentrations of 15-keto-dihydro PGF_2α in 91 IPF patients and compared these values with those of controls (n = 25). We further investigated the relationships of plasma 15-keto-dihydro PGF_2α concentrations with disease severity and mortality.</p><p>Results</p><p>Plasma concentrations of 15-keto-dihydro PGF_2α were significantly higher in IPF patients than controls (<i>p</i><0.001). Plasma concentrations of this metabolite were significantly correlated with forced expiratory volume in 1 second (<i>Rs</i> [correlation coefficient] = −0.34, <i>p</i> = 0.004), forced vital capacity (<i>Rs</i> = −0.33, <i>p</i> = 0.005), diffusing capacity for carbon monoxide (<i>Rs</i> = −0.36, <i>p</i> = 0.003), the composite physiologic index (<i>Rs</i> = 0.40, <i>p</i> = 0.001), 6-minute walk distance (<i>Rs</i> = −0.24, <i>p</i> = 0.04) and end-exercise oxygen saturation (<i>Rs</i> = −0.25, <i>p</i> = 0.04) when patients with emphysema were excluded. Multivariate analysis using stepwise Cox proportional hazards model showed that a higher composite physiologic index (relative risk = 1.049, <i>p</i> = 0.002) and plasma 15-keto-dihydro PGF_2α concentrations (relative risk = 1.005, <i>p</i> = 0.002) were independently associated with an increased risk of mortality.</p><p>Conclusions</p><p>We demonstrated significant associations of plasma concentrations of PGF_2α metabolites with disease severity and prognosis, which support a potential pathogenic role for PGF_2α in human IPF.</p></div

Relationships between plasma 15-keto-dihydro prostaglandin F_2α concentrations and clinical parameters in patients with idiopathic pulmonary fibrosis.

*<p>Time from diagnosis to blood sample collection.</p><p>FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; DL_CO, diffusing capacity for carbon monoxide; PaCO₂, arterial partial pressure of carbon dioxide; PaO₂, arterial partial pressure of oxygen; A-aDO₂, alveolar-arterial oxygen pressure difference.</p

Correlations of plasma 15-keto-dihydro prostaglandin F_2α concentrations with indices of disease severity.

<p>Scatter diagrams show the correlations of plasma 15-keto-dihydro prostaglandin F_2α concentrations with FVC (a), DL_CO (b), six-minute walk distance (c) and end-exercise oxygen saturation (d) in IPF patients without emphysema. The <i>Rs</i> value indicates the correlation coefficient.</p

Characteristics of patients and controls.

<p>Data are presented as mean±standard deviation.</p>*<p>Comparison between all patients and controls.</p>**<p>Time from diagnosis to blood sample collection.</p><p>BMI, body mass index; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; DL_CO, diffusing capacity for carbon monoxide; PaCO₂, arterial partial pressure of carbon dioxide; PaO₂, arterial partial pressure of oxygen; A-aDO₂, alveolar-arterial oxygen pressure difference; SP-D, surfactant protein-D; PGF_2α, prostaglandin F_2α; NA, not available.</p

Cox proportional hazard model results for evaluating the risk of mortality.

<p>CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; DL_CO, diffusing capacity for carbon monoxide; SP-D, surfactant protein-D; PGF_2α, prostaglandin F_2α.</p