Astrocytic STAT3 activation and chronic itch require IP3R1\/TRPC-dependent Ca21\u00a0signals in mice<\/p>\n\n\n\n
Miho Shiratori-Hayashi, PhD,a\u00a0Chiharu Yamaguchi, MPharm,a\u00a0Kazushi Eguchi, MPharm,a\u00a0Yuto Shiraishi, BPharm,a\u00a0Keita Kohno, BPharm,a\u00a0Katsuhiko Mikoshiba, MD, PhD,b,c,d\u00a0Kazuhide Inoue, PhD,e\u00a0Motohiro Nishida, PhD,f,g\u00a0and Makoto Tsuda, PhDa\u00a0<\/p>\n\n\n\n
Background: Chronic itch is a debilitating symptom of inflammatory skin diseases, but the underlying mechanism is poorly understood. We have recently demonstrated that astrocytes in the spinal dorsal horn become reactive in models of atopic and contact dermatitis via activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) and critically contribute to chronic itch. In general, STAT3 is transiently activated; however, STAT3 activation in reactive astrocytes of chronic itch model mice persistently occurs via an unknown mechanism.
Objective: We aimed to determine the mechanisms of persistent activation of astrocytic STAT3 in chronic itch conditions. Methods: To determine the factors that are required for persistent activation of astrocytic STAT3, Western blotting and calcium imaging with cultured astrocytes or spinal cord slices were performed. Thereafter, chronic itch model mice were used for genetic and behavioral experiments to confirm the role of the factors determined to mediate persistent STAT3 activation from\u00a0in vitro\u00a0and\u00a0ex vivo\u00a0experiments in chronic itch.<\/p>\n\n\n\n
Results: IP3\u00a0receptor type 1 (IP3R1) knockdown in astrocytes suppressed IL-6\u2013induced persistent STAT3 activation and expression of lipocalin-2 (LCN2), an astrocytic STAT3- dependent inflammatory factor that is required for chronic itch. IP3R1-dependent astrocytic Ca21\u00a0responses involved Ca21\u00a0influx through the cation channel transient receptor potential canonical (TRPC), which was required for persistent STAT3 activation evoked by IL-6. IL-6 expression was upregulated in dorsal root ganglion neurons in a mouse model of chronic itch. Dorsal root ganglion neuron\u2013specific IL-6 knockdown, spinal astrocyte\u2013specific IP3R1 knockdown, and pharmacologic spinal TRPC inhibition attenuated LCN2 expression and chronic itch. <\/p>\n\n\n\n
Conclusion: Our findings suggest that IP3R1\/TRPC channel\u2013 mediated Ca21\u00a0signals elicited by IL-6 in astrocytes are necessary for persistent STAT3 activation, LCN2 expression, and chronic itch, and they may also provide new targets for therapeutic intervention. (J Allergy Clin Immunol 2021;147:1341-53.)<\/p>\n\n\n\n
Key words: Contact dermatitis, chronic itch, astrocytes, STAT3, lip- ocalin-2, Ca21 signal, IP3R1, TRPC, IL-6, primary afferent sensory neuron<\/p>\n\n\n\n
<\/p>\n\n\n\n
<\/p>\n","protected":false},"excerpt":{"rendered":"
Astrocytic STAT3 activation and chronic itch require IP3R1\/TRPC-dependent Ca21\u00a0signals in mice Miho Shiratori-Hayashi, PhD,a\u00a0Chiharu Yamaguchi, MPharm,a\u00a0Kazushi Eguchi, MPharm,a\u00a0Yuto Shiraishi, BPharm,a\u00a0Keita Kohno, BPharm,a\u00a0Katsuhiko Mikoshiba, MD, PhD,b,c,d\u00a0Kazuhide Inoue, PhD,e\u00a0Motohiro Nishida, PhD,f,g\u00a0and Makoto Tsuda, PhDa\u00a0 Background: Chronic itch is a debilitating symptom of inflammatory skin diseases, but the underlying mechanism is poorly understood. We have recently demonstrated that […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}}},"categories":[1],"tags":[],"_links":{"self":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2237"}],"collection":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2237"}],"version-history":[{"count":1,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2237\/revisions"}],"predecessor-version":[{"id":2239,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2237\/revisions\/2239"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2237"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2237"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2237"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}