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Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism

2024; Elsevier BV; Volume: 26; Issue: 10 Linguagem: Inglês

10.1016/j.jcyt.2024.05.010

1477-2566

Hazel Dunbar, Ian J. Hawthorne, Courteney Tunstead, Eóin N. McNamee, Daniel J. Weiss, Michelle E. Armstrong, Seamas C. Donnelly, Karen English,

Macrophage Migration Inhibitory Factor

Trained immunity (TI) results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous stimuli. We have previously shown that HDM-induced innate training was amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT7 functional polymorphism. This study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo.Compared to wildtype mice, in vivo house dust mite-primed bone marrow-derived macrophages (BMDMs) from CATT7 mice expressed significantly higher levels of M1 associated genes following LPS stimulation ex vivo. Transwell co-cultures of CATT7 BMDMs with MSCs suppressed this HDM-primed effect, with TNFα being significantly decreased in a COX-2 dependent manner. Interestingly, IL-6 was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT7 BMDMs when co-cultured at time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an over-zealous, human MIF-dependent immune response. Utilising an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and 11 suppressed this trained phenomenon, by significantly reducing TNFα, and reducing IL-6 and CCL17 production.This novel study elucidates how MSCs can attenuate a MIF-driven, HDM-trained response in CATT7 mice, in a model of allergic airway inflammation.