Dunbar, Hazel and Hawthorne, Ian J. and McNamee, Eóin N. and Armstrong, Michelle E. and Donnelly, Seamas C. and English, Karen (2024) The human MIF polymorphism CATT7 enhances pro‐inflammatory macrophage polarization in a clinically relevant model of allergic airway inflammation. The FASEB Journal, 38 (6). ISSN 0892-6638

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Abstract

High level expression of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been associated with severe asthma. The role of MIF and its functional promotor polymorphism in innate immune training is currently unknown. Using novel humanized CATT7 MIF mice, this study is the first to investigate the effect of MIF on bone marrow-derived macrophage (BMDM) memory after house dust mite (HDM) challenge. CATT7 BMDMs demonstrated a significant primed increase in M1 markers following HDM and LPS stimulation, compared to naive mice. This M1 signature was found to be MIF-dependent, as administration of a small molecule MIF inhibitor, SCD-19, blocked the induction of this pro-inflammatory M1-like phenotype in BMDMs from CATT7 mice challenged with HDM. Training naive BMDMs in vitro with HDM for 24 h followed by a rest period and subsequent stimulation with LPS led to significantly increased production of the pro-inflammatory cytokine TNFα in BMDMs from CATT7 mice but not WT mice. Addition of the pan methyltransferase inhibitor MTA before HDM training significantly abrogated this effect in BMDMs from CATT7 mice, suggesting that HDM-induced training is associated with epigenetic remodelling. These findings suggest that trained immunity induced by HDM is under genetic control, playing an important role in asthma patients with the high MIF genotypes (CATT6/7/8).

Item Type:	Article
Keywords:	bone marrow-derived macrophages; house dust mite; innate immunity; innate priming; innatetraining; macrophage migration inhibitory facto; polarization;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	18555
Identification Number:	https://doi.org/10.1096/fj.202400207R
Depositing User:	Karen English
Date Deposited:	21 May 2024 13:04
Journal or Publication Title:	The FASEB Journal
Publisher:	Wiley
Refereed:	Yes
Funders:	Irish Research Council, Grant/AwardNumber: IRCLA/2017/288; MaynoothUniversity HEA COVID-19 CostedExtensions Fund; Science FoundationIreland (SFI), Grant/Award Number:12/RI/2346
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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