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Human CATT7 allele exacerbates airway inflammation in a house dust mite model of allergic asthma. (A) Representative images of lung tissue stained with periodic acid Schiff at 20× magnification, scale bar = 20 μm. (B) Goblet cell hyperplasia was investigated through the quantitation of PAS‐positive cells. (C) Representative images of lung tissue stained with Masson's trichrome at 4× magnification, scale bar = 200 μm. (D) Quantitation of % subepithelial collagen. (E) Representative images of lung tissue stained with H&E from WT, 5CATT, and 7CATT mice challenged with HDM or PBS control at 20× magnification, scale bar = 20 μm. (F) Quantitation of airway inflammation in H&E‐stained lung tissue. Data are presented as mean ±$$ \pm $$ SEM; N = 6 per group. *p < .05; **p < .01; ***p < .001; ****p < .0001.

Human CATT7 allele exacerbates airway inflammation in a house dust mite model of allergic asthma. (A) Representative images of lung tissue stained with periodic acid Schiff at 20× magnification, scale bar = 20 μm. (B) Goblet cell hyperplasia was investigated through the quantitation of PAS‐positive cells. (C) Representative images of lung tissue stained with Masson's trichrome at 4× magnification, scale bar = 200 μm. (D) Quantitation of % subepithelial collagen. (E) Representative images of lung tissue stained with H&E from WT, 5CATT, and 7CATT mice challenged with HDM or PBS control at 20× magnification, scale bar = 20 μm. (F) Quantitation of airway inflammation in H&E‐stained lung tissue. Data are presented as mean ±$$ \pm $$ SEM; N = 6 per group. *p < .05; **p < .01; ***p < .001; ****p < .0001.

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Macrophage migration inhibitory factor (MIF) expression is controlled by a functional promoter polymorphism, where the number of tetranucleotide repeats (CATTn) corresponds to the level of MIF expression. To examine the role of this polymorphism in a pre‐clinical model of allergic asthma, novel humanized MIF mice with increasing CATT repeats (CATT5...

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... Low expression of MIF is associated with a low number of repeats of the tetranucleotide repeat polymorphism 'CATT' located within the promoter region of the MIF gene [40]. Using novel humanised MIF mice expressing the 7-repeat allele termed CATT 7 , we have shown that high expression of human MIF drives airway inflammation following the house dust mite (HDM) challenge [41]. Our group has also demonstrated the ability of CATT 7 -MIF licensing to enhance MSCs immunomodulatory effects in vivo [42]. ...
... Aliquots were stored at −20 • C. Aliquots were not freeze-thawed. To account for the variability of human MIF levels between CATT 7 mice and to verify that WT mice did not produce human MIF, supernatants were measured by human MIF ELISA (R&D) [41]. ...
Article
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Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)‐licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)‐driven allergic asthma. Soluble mediators released into the MSC secretome boast cytoprotective properties equal to those associated with the cell itself. In asthma, epithelial barrier damage caused by the inhalation of allergens like HDM drives goblet cell hyperplasia. Vascular endothelial growth factor (VEGF) plays a pivotal role in the repair and maintenance of airway epithelial integrity. Human bone marrow‐derived MSCs expressed the MIF receptors CD74, CXCR2, and CXCR4. Endogenous MIF from high MIF expressing CATT7 bone marrow‐derived macrophages increased MSC production of VEGF through the MIF CXCR4 chemokine receptor, where preincubation with CXCR4 inhibitor mitigated this effect. CATT7‐MIF licensed MSC conditioned media containing increased levels of VEGF significantly enhanced bronchial epithelial wound healing via migration and proliferation in vitro. Blocking VEGFR2 or the use of mitomycin C abrogated this effect. Furthermore, CATT7‐MIF MSC CM significantly decreased goblet cell hyperplasia after the HDM challenge in vivo. This was confirmed to be VEGF‐dependent, as the use of anti‐human VEGF neutralising antibody abrogated this effect. Overall, this study highlights that MIF‐licenced MSCs show enhanced production of VEGF, which has the capacity to repair the lung epithelium.
... The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is associated with a range of inflammatory diseases, including sepsis, autoimmune disease and severe asthma [10À12]. The MIF CATT 7 allele correlates with high MIF expression [4,13]. We have demonstrated exacerbated HDM-induced airway inflammation in mice expressing the human MIF CATT 7 allele [4,6]. ...
... The MIF CATT 7 allele correlates with high MIF expression [4,13]. We have demonstrated exacerbated HDM-induced airway inflammation in mice expressing the human MIF CATT 7 allele [4,6]. Recently, using in vitro assays and an in vivo model of trained immunity, we identified a novel role for the high-expression MIF CATT 7 allele in significantly enhancing HDM-induced trained immunity in mouse bone marrow-derived macrophages (BMDMs) [5]. ...
... Human MIF-expressing CATT 7 mice and wild-type (WT) littermate controls were challenged with 25 mg of HDM intranasally as previously described [4,6]. ...
... MIF's involvement in asthma severity has been linked to a functional promotor polymorphism, where an increase in the number of repeats of a tetranucleotide sequence (CATT) n , correlates with increased MIF expression. [17][18][19] Humans that possess a five-repeat allele of this MIF polymorphism have been noted to have a milder subtype of disease. 20 Interestingly, an association between severe human asthma and high expression MIF alleles has been documented, 21,22 with ~50% of asthma patients expressing the 6/7/8 CATT allele, 23 compared to 19%-20% of healthy controls. ...
... We have previously illustrated the role of the high expressing human CATT 7 MIF allele in a model of house dust mite (HDM)-induced allergic airway inflammation. 18,19 This study is the first to characterize the macrophage phenotype in these novel human CATT 7 MIF expressing transgenic mice, comparing the macrophage activation status from both naive mice and those exposed to an acute model of HDM-induced asthma. Furthermore, this study is the first to identify the role of this high expressing human MIF polymorphism in the trained innate immune system of these mice after HDM exposure. ...
... Within this human MIF gene, 794 downstream of the promotor region, the number of tetranucleotide repeats correlates with MIF allele expression, 17 where seven repeats of this tetranucleotide sequence "CATT" generated CATT 7 mice, containing the high expressing MIF allele. 18,19 To characterize pathological differences associated with the expression of the human MIF polymorphism after intranasal administration of HDM or PBS control in a model of allergic airway inflammation ( Figure 1A), cell populations in the BALF were identified by carrying out differential cell counts and identifying infiltrated immune cells based on their morphology. BALF from HDM-challenged CATT 7 mice exhibited significantly elevated numbers of immune cells, predominately eosinophils rather than lymphocytes, neutrophils, or macrophages, compared to WT mice ( Figure 1B). ...
Article
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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).
... Asthma is induced by inflammation, remodeling, and hyperresponsiveness of the airways [21,22]. Airway hyperreactivity includes intense constriction of the airways and airway spasm. ...
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Background Yanghe Pingchuan decoction (YPD) has been used for asthma treatment for many years in China. We sought to understand the mechanism of YPD, and find more potential targets for YPD-based treatment of asthma. Methods An ovalbumin-induced asthma model in rats was created. Staining (hematoxylin and eosin, Masson) was used to evaluate the treatment effect of YPD. RNA-sequencing was carried out to analyze global gene expression, and differentially expressed genes (DEGs) were identified. Analysis of the functional enrichment of genes was done using the Gene Ontology database (GO). Analysis of signaling-pathway enrichment of genes was done using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Real-time reverse transcription-quantitative polymerase chain reaction was undertaken to measure expression of DEGs. Results Pathology showed that YPD had an improvement effect on rats with asthma. RNA-sequencing showed that YPD led to upregulated and downregulated expression of many genes. The YPD-based control of asthma pathogenesis may be related to calcium ion (Ca2+) binding, inorganic cation transmembrane transporter activity, microtubule motor activity, and control of canonical signaling (e.g., peroxisome proliferator-activated receptor, calcium, cyclic adenosine monophosphate). Enrichment analyses suggested that asthma pathogenesis may be related to Ca2 + binding and contraction of vascular smooth muscle. A validation experiment showed that YPD could reduce the Ca2 + concentration by inhibiting the Angiopoietin-II (Ang-II)/Phospholipase (PLA)/calmodulin (CaM0 signaling axis. Conclusion Control of asthma pathogenesis by YPD may be related to inhibition of the Ang-II/PLA/CaM signaling axis, reduction of the Ca²⁺ concentration, and relaxation of airway smooth muscle (ASM).
... Our previous work established a dominant role of MIF allelic variants in the severity of HDM-induced allergic asthma. 62 Using humanized high-expressing and low-expressing MIF mice in an HDM model of allergic airway inflammation, we demonstrated the pivotal role MIF plays in exacerbating asthma pathogenesis. High levels of human MIF resulted in a significant increase in airway inflammation as a result of elevated levels of Th2 cytokines promoting infiltration of eosinophils into the airways. ...
... To account for variability of hMIF levels between CATT 7 mice and to ensure that WT mice did not produce hMIF, CATT 7 , CATT 5 , and WT supernatants were measured by hMIF ELISA (R&D Systems, MN, USA) as described previously ( Figure S2). 62 5 Â 10 4 licensed MSCs were administered i.v. into HDM-challenged CATT 7 mice on day 14. ...