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

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) CATT 7 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 CATT 7 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.