Universität zu Köln

Redhu, Davender ORCID: 0000-0002-8423-0844, Franke, Kristin, Aparicio-Soto, Marina, Kumari, Vandana, Pazur, Kristijan ORCID: 0000-0002-3959-6986, Illerhaus, Anja, Hartmann, Karin ORCID: 0000-0002-4595-8226, Worm, Margitta and Babina, Magda ORCID: 0000-0002-4500-7615 (2022). Mast cells instruct keratinocytes to produce thymic stromal lymphopoietin: Relevance of the tryptase/protease-activated receptor 2 axis. J. Allergy Clin. Immunol., 149 (6). S. 2053 - 2068. NEW YORK: MOSBY-ELSEVIER. ISSN 1097-6825

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Abstract

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. Objective: We investigated whether and by what mechanisms mast cells (MCs) foster TSLP responses in the cutaneous environment. Methods: Ex vivo and in vivo skin 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-coupled 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 acted 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Redhu, Davender UNSPECIFIED orcid.org/0000-0002-8423-0844 UNSPECIFIED Franke, Kristin UNSPECIFIED UNSPECIFIED UNSPECIFIED Aparicio-Soto, Marina UNSPECIFIED UNSPECIFIED UNSPECIFIED Kumari, Vandana UNSPECIFIED UNSPECIFIED UNSPECIFIED Pazur, Kristijan UNSPECIFIED orcid.org/0000-0002-3959-6986 UNSPECIFIED Illerhaus, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Karin UNSPECIFIED orcid.org/0000-0002-4595-8226 UNSPECIFIED Worm, Margitta UNSPECIFIED UNSPECIFIED UNSPECIFIED Babina, Magda UNSPECIFIED orcid.org/0000-0002-4500-7615 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-687647
DOI:	10.1016/j.jaci.2022.01.029
Journal or Publication Title:	J. Allergy Clin. Immunol.
Volume:	149
Number:	6
Page Range:	S. 2053 - 2068
Date:	2022
Publisher:	MOSBY-ELSEVIER
Place of Publication:	NEW YORK
ISSN:	1097-6825
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN EPITHELIAL-CELLS; ATOPIC-DERMATITIS; HUMAN SKIN; TSLP; INFLAMMATION; EXPRESSION; PROTEASES; HISTAMINE; ALPHA; INDUCTION Multiple languages Allergy; Immunology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68764