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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1429009

Histamine and Th2 cytokines independently and synergistically upregulate MMP12 expression in human M2 macrophages

Provisionally accepted
Alice Pereira Da Fonseca Alice Pereira Da Fonseca 1*Stephan Traidl Stephan Traidl 1Ralf Gutzmer Ralf Gutzmer 1,2Katrin Schaper-Gerhardt Katrin Schaper-Gerhardt 1,2Thomas Werfel Thomas Werfel 1Susanne Mommert Susanne Mommert 1
  • 1 Hannover Medical School, Hanover, Germany
  • 2 Johannes Wesling Klinik, Minden, Germany

The final, formatted version of the article will be published soon.

    Beyond Th2 cells and various immune cells, M2 macrophages have been identified in lesional skin of atopic dermatitis (AD) indicating their involvement in the disease’s underlying mechanisms. MMP12, a matrix-degrading enzyme, which is predominantly produced by macrophages, is increased in skin lesions of AD patients. In this study we investigated the expression of MMP12 mRNA in lesional AD skin at single cell level through RNA sequencing (scRNA-seq) and the expression of MMP12 in M2 macrophages from healthy individuals and AD patients in response to Th2 cytokines and histamine using quantitative PCR and ELISA. Additionally, we analyzed macrophages from dupilumab-treated AD patients using the same methods to assess the influence of Th2 cytokines on MMP12 expression ex-vivo. ScRNA-seq identified macrophages as the primary producer of MMP12 in lesional AD skin. In-vitro, both MMP12 mRNA and protein expression were significantly increased in monocytes during differentiation to M2 macrophages in the presence of histamine, of Th2 cytokines or of Th2 cytokines in combination with histamine. In M2 macrophages obtained from dupilumab-treated AD patients, the upregulation of MMP12 expression by IL-4 and IL-13 was attenuated. Our findings unveil a novel mechanism whereby Th2 cytokines and histamine regulate MMP12 expression, potentially impacting skin barrier homeostasis in AD.

    Keywords: atopic dermatitis, Macrophages, MMP12, Histamine, Th2 cytokines, Dupilumab

    Received: 07 May 2024; Accepted: 30 Aug 2024.

    Copyright: © 2024 Pereira Da Fonseca, Traidl, Gutzmer, Schaper-Gerhardt, Werfel and Mommert. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Alice Pereira Da Fonseca, Hannover Medical School, Hanover, Germany

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.