Browsing by Author "Nanri, Yasuhiro"

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    Constitutive overexpression of periostin delays wound healing in mouse skin
    (Wiley, 2018) Nunomura, Satoshi; Nanri, Yasuhiro; Ogawa, Masahiro; Arima, Kazuhiko; Mitamura, Yasutaka; Yoshihara, Tomohito; Hasuwa, Hidetoshi; Conway, Simon J.; Izuhara, Kenji; Pediatrics, School of Medicine
    Periostin is a matricellular protein involved in development, maintenance and regulation of tissues and organs via by binding to cell surface integrin receptors. Pathologically, periostin plays an important role in the process of wound healing: as a deficiency of the Postn gene delays wound closure and periostin is consistently upregulated in response to injury and skin diseases. However, the functional role of elevated periostin in the process of wound healing has not been tested. In this study, we generated Postn-transgenic mice under the control of the CAG promoter/enhancer to investigate the effects of constitutive overexpression of full length periostin during its pathophysiological roles. Transgenic mice showed significant overexpression of periostin in skin, lung, and heart, but no morphological changes were observed. However, when these transgenic mice were injured, periostin overexpression delayed the closure of excisional wounds. Expression of IL-1β and TNFα, pro-inflammatory cytokines important for wound healing, was significantly decreased in the transgenic mice, prior to delayed healing. Infiltration of neutrophils and macrophages, the main sources of IL-1β and TNFα, was also downregulated in the transgenic wound sites. From these data, we conclude that enforced expression of periostin delays wound closure due to reduced infiltration of neutrophils and macrophages followed by downregulation of IL-1β and TNFα expression. This suggests that regulated spatiotemporal expression of periostin is important for efficient wound healing and that constitutive periostin overexpression interrupts the normal process of wound closure.
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    Cross-Talk between Transforming Growth Factor-β and Periostin Can Be Targeted for Pulmonary Fibrosis
    (American Thoracic Society, 2020-02) Nanri, Yasuhiro; Nunomura, Satoshi; Terasaki, Yasuhiro; Yoshihara, Tomohito; Hirano, Yusuke; Yokosaki, Yasuyuki; Yamaguchi, Yukie; Feghali-Bostwick, Carol; Ajito, Keiichi; Murakami, Shoichi; Conway, Simon J.; Izuhara, Kenji; Pediatrics, School of Medicine
    Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to learn whether the cross-talk between TGF-β (transforming growth factor-β), a central mediator in pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether inhibitors for integrin αVβ3, a periostin receptor, can block pulmonary fibrosis in model mice and the TGF-β signals in fibroblasts from patients with IPF. We found that cross-talk exists between TGF-β and periostin signals via αVβ3/β5 converging into Smad3. This cross-talk is necessary for the expression of TGF-β downstream effector molecules important for pulmonary fibrosis. Moreover, we identified several potent integrin low-molecular-weight inhibitors capable of blocking cross-talk with TGF-β signaling. One of the compounds, CP4715, attenuated bleomycin-induced pulmonary fibrosis in vivo in mice and the TGF-β signals in vitro in fibroblasts from patients with IPF. These results suggest that the cross-talk between TGF-β and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block this cross-talk.
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    Periostin activates distinct modules of inflammation and itching downstream of the type 2 inflammation pathway
    (Elsevier, 2023) Nunomura, Satoshi; Uta, Daisuke; Kitajima, Isao; Nanri, Yasuhiro; Matsuda, Kosuke; Ejiri, Naoko; Kitajima, Midori; Ikemitsu, Hitoshi; Koga, Misaki; Yamamoto, Sayaka; Honda, Yuko; Takedomi, Hironobu; Andoh, Tsugunobu; Conway, Simon J.; Izuhara, Kenji; Pediatrics, School of Medicine
    Atopic dermatitis (AD) is a chronic relapsing skin disease accompanied by recurrent itching. Although type 2 inflammation is dominant in allergic skin inflammation, it is not fully understood how non-type 2 inflammation co-exists with type 2 inflammation or how type 2 inflammation causes itching. We have recently established the FADS mouse, a mouse model of AD. In FADS mice, either genetic disruption or pharmacological inhibition of periostin, a downstream molecule of type 2 inflammation, inhibits NF-κB activation in keratinocytes, leading to downregulating eczema, epidermal hyperplasia, and infiltration of neutrophils, without regulating the enhanced type 2 inflammation. Moreover, inhibition of periostin blocks spontaneous firing of superficial dorsal horn neurons followed by a decrease in scratching behaviors due to itching. Taken together, periostin links NF-κB-mediated inflammation with type 2 inflammation and promotes itching in allergic skin inflammation, suggesting that periostin is a promising therapeutic target for AD.