Mast cells instruct keratinocytes to produce thymic stromal lymphopoietin: Relevance of the tryptase\/protease-activated receptor 2 axis<\/p>\n\n\n\n
Davender Redhu, PhD,a\u00a0Kristin Franke, PhD,a\u00a0Marina Aparicio-Soto, PhD,a\u00a0Vandana Kumari, PhD,a\u00a0Kristijan Pazur, PhD,a\u00a0Anja Illerhaus, PhD,b\u00a0Karin Hartmann, MD,c,d\u00a0Margitta Worm, MD,a\u00a0and Magda Babina, PhDa\u00a0Berlin and Cologne, Germany; and Basel, Switzerland<\/p>\n\n\n\n
Background: Thymic stromal lymphopoietin (TSLP) promotes TH2 inflammation and is deeply intertwined with inflammatory dermatoses like atopic dermatitis. The mechanisms regulating TSLP are poorly defined.<\/p>\n\n\n\n
Objective: We investigated whether and by what mechanisms mast cells (MCs) foster TSLP responses in the cutaneous environment.
Methods:\u00a0Ex vivo\u00a0and\u00a0in vivo\u00a0skin MC degranulation was induced by compound 48\/80 in wild-type protease-activated receptor 2 (PAR-2)- and MC-deficient mice in the presence or absence of neutralizing antibodies, antagonists, or exogenous mouse MC protease 6 (mMCP6). Primary human keratinocytes and murine skin explants were stimulated with lysates\/supernatants of human skin MCs, purified tryptase, or MC lysate diminished of tryptase. Chymase and histamine were also used. TSLP was quantified by ELISA, real-time quantitative PCR, and immunofluorescence staining.
Results: Mas-related G protein\u2013coupled receptor X2 (Mrgprb2) activation elicited TSLP in intact skin, mainly in the epidermis. Responses were strictly MC dependent and relied on PAR-2. Complementarily, TSLP was elicited by tryptase in murine skin explants. Exogenous mMCP6 could fully restore responsiveness in MC-deficient murine skin explants. Conversely, PAR-2 knockout mice were unresponsive to mMCP6 while displaying increased responsiveness to other inflammatory pathways, such as IL-1a. Indeed, IL-1a\u00a0acted in concert with tryptase. In primary human keratinocytes, MC-elicited TSLP generation was likewise abolished by tryptase inhibition or elimination. Chymase and histamine did not affect TSLP production, but histamine triggered IL-6, IL- 8, and stem cell factor.
Conclusion: MCs communicate with kerationocytes more broadly than hitherto suspected. The tryptase\/PAR-2 axis is a crucial component of this cross talk, underlying MC-dependent stimulation of TSLP in neighboring kerationocytes. Interference specifically with MC tryptase may offer a treatment option for disorders initiated or perpetuated by aberrant TSLP, such as atopic dermatitis. (J Allergy Clin Immunol 2022;nnn:nnn-nnn.)<\/p>\n\n\n\n
Key words: Atopic dermatitis, interleukin 1, keratinocytes, mast cells, PAR-2, TSLP, tryptase<\/p>\n","protected":false},"excerpt":{"rendered":"
Mast cells instruct keratinocytes to produce thymic stromal lymphopoietin: Relevance of the tryptase\/protease-activated receptor 2 axis Davender Redhu, PhD,a\u00a0Kristin Franke, PhD,a\u00a0Marina Aparicio-Soto, PhD,a\u00a0Vandana Kumari, PhD,a\u00a0Kristijan Pazur, PhD,a\u00a0Anja Illerhaus, PhD,b\u00a0Karin Hartmann, MD,c,d\u00a0Margitta Worm, MD,a\u00a0and Magda Babina, PhDa\u00a0Berlin and Cologne, Germany; and Basel, Switzerland Background: Thymic stromal lymphopoietin (TSLP) promotes TH2 inflammation and is deeply intertwined with […]<\/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\/2499"}],"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=2499"}],"version-history":[{"count":1,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2499\/revisions"}],"predecessor-version":[{"id":2501,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2499\/revisions\/2501"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2499"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2499"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2499"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}