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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cytokines and Soluble Mediators in Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1419117

Development of human innate immune responses in a humanized mouse model expressing four human myelopoiesis transgenes

Provisionally accepted
Hannah Stocks Hannah Stocks 1Linos Vandekerckhove Linos Vandekerckhove 2Geert Van Loo Geert Van Loo 1Andy Wullaert Andy Wullaert 3*
  • 1 Ghent University, Ghent, East Flanders, Belgium
  • 2 Ghent University Hospital, Ghent, East Flanders, Belgium
  • 3 University of Antwerp, Antwerp, Belgium

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

    Background Dysregulated innate immune responses underlie multiple inflammatory diseases, but clinical translation of preclinical innate immunity research in mice is hampered by the difficulty of studying human inflammatory reactions in an in vivo context. We therefore sought to establish in vivo human inflammatory responses in NSG-QUAD mice that express four human myelopoiesis transgenes to improve engraftment of a human innate immune system.We reconstituted NSG-QUAD mice with human hematopoietic stem and progenitor cells (HSPCs), after which we evaluated human myeloid cell development and subsequent human responses to systemic and local lipopolysaccharide (LPS) challenges.Results NSG-QUAD mice already displayed engraftment of human monocytes, dendritic cells and granulocytes in peripheral blood, spleen and liver at 6 weeks after HSPC reconstitution, in which both classical, intermediate and non-classical monocytes were present. These huNSG-QUAD mice responded to intraperitoneal and intranasal LPS challenges with production of NF-κB-dependent human cytokines, a human type I interferon response, as well as inflammasome-mediated production of human IL-1β and IL-18. The latter were specifically abrogated by the NLRP3 inhibitor MCC950, while LPS-induced human monocyte death was not altered. Besides providing proof-of-principle for small molecule testing of human inflammatory reactions in huNSG-QUAD mice, this observation suggests that LPS-induced in vivo release of human NLRP3 inflammasome-generated cytokines occurs in a cell death-independent manner.HuNSG-QUAD mice are competent for the NF-κB, interferon and inflammasome effectors of human innate immunity, and can thus be utilized to investigate signaling mechanisms and pharmacological targeting of human inflammatory responses in an in vivo setting.

    Keywords: humanized mice, innate immunity, Myeloid Cells, Cytokines, inflammasome. 2

    Received: 17 Apr 2024; Accepted: 09 Sep 2024.

    Copyright: © 2024 Stocks, Vandekerckhove, Van Loo and Wullaert. 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: Andy Wullaert, University of Antwerp, Antwerp, Belgium

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