Mast cells instruct keratinocytes to produce thymic stromal lymphopoietin: Relevance of the tryptase/protease-activated receptor 2 axis

Davender Redhu; Kristin Franke; Marina Aparicio-Soto; Vandana Kumari; Kristijan Pazur; Anja Illerhaus; Karin Hartmann; Margitta Worm; Magda Babina

doi:10.1016/j.jaci.2022.01.029

Mast cells instruct keratinocytes to produce thymic stromal lymphopoietin: Relevance of the tryptase/protease-activated receptor 2 axis

J Allergy Clin Immunol. 2022 Jun;149(6):2053-2061.e6. doi: 10.1016/j.jaci.2022.01.029. Epub 2022 Mar 1.

Authors

Davender Redhu¹, Kristin Franke¹, Marina Aparicio-Soto¹, Vandana Kumari¹, Kristijan Pazur¹, Anja Illerhaus², Karin Hartmann³, Margitta Worm⁴, Magda Babina⁵

Affiliations

¹ Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
² Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
³ Department of Dermatology, Division of Allergy, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
⁴ Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address: margitta.worm@charite.de.
⁵ Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address: magda.babina@charite.de.

PMID: 35240143
DOI: 10.1016/j.jaci.2022.01.029

Abstract

Background: Thymic stromal lymphopoietin (TSLP) promotes T_H2 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-1α. Indeed, IL-1α 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.

Keywords: Atopic dermatitis; PAR-2; TSLP; interleukin 1; keratinocytes; mast cells; tryptase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chymases / metabolism
Cytokines / metabolism
Dermatitis, Atopic*
Histamine / metabolism
Humans
Keratinocytes / metabolism
Mast Cells / metabolism
Mice
Receptor, PAR-2* / genetics
Receptor, PAR-2* / metabolism
Thymic Stromal Lymphopoietin
Tryptases / metabolism

Substances

Cytokines
Receptor, PAR-2
TSLP protein, human
Histamine
Chymases
Tryptases
Thymic Stromal Lymphopoietin