Protection against lung pathology during obesity-accelerated ageing in mice by the parasitic worm product ES-62

Harnett, Margaret M. and Lumb, Felicity E. and Crowe, Jenny and Doonan, James and Buitrago, Geraldine and Brown, Stephanie and Thom, Gillian and MacDonald, Amy and Suckling, Colin J. and Selman, Colin and Harnett, William (2023) Protection against lung pathology during obesity-accelerated ageing in mice by the parasitic worm product ES-62. Frontiers in Immunology-Inflammation, 14. 1285069. ISSN 1664-3224 (https://doi.org/10.3389/fimmu.2023.1285069)

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Abstract

Mice develop pathology in the lungs as they age and this may be accelerated by a high calorie diet (HCD). ES-62 is a protein secreted by the parasitic worm Acanthocheilonema viteae that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties. In this study, we show that weekly treatment of C57BL/6j mice with ES-62 protected against pathology in the lungs in male but not female mice fed a HCD from 10 weeks of age as shown by reductions in cellular infiltration and airway remodelling, particularly up to 160 days of age. ES-62 also reduced gene expression of the cytokines IL-4 and IL-17 and in addition the TLR/IL-1R adaptor MyD88, in the lungs of male mice although HCD-induced increases in these inflammatory markers were not detected until between 340 and 500 days of age. A combination of two drug-like ES-62 PC-based small molecule analogues, produced broadly similar protective effects in the lungs of male mice with respect to both lung pathology and inflammatory markers, in addition to a decrease in HCD-induced IL-5 expression. Overall, our data show that ES-62 and its SMAs offer protection against HCD-accelerated pathological changes in the lungs during ageing. Given the targeting of Th2 cytokines and IL-17, we discuss this protection in the context of ES-62’s previously described amelioration of airway hyper-responsiveness in mouse models of asthma.

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