The LA-NF-κB-ILC2 axis exacerbates intestinal milk protein allergy in mice by promoting ILC2 activation.

Abstract

OBJECTIVE: Cow milk protein allergy (CMPA), a common food allergy in early childhood, involves type 2 immune cells such as group 2 innate lymphoid cells (ILC2s). Linoleic acid (LA) is a polyunsaturated fatty acid with immunomodulatory properties. Although its role in CMPA is not yet clear, previous metabolomics research by our team revealed elevated levels of linoleic acid in the intestinal ILC2s of allergic mice. In this study, the effects of linoleic acid on ILC2 activation and the mechanisms underlying this activation were explored using a mouse model of CMPA. METHODS: The linoleic acid content of intestinal ILC2s from milk protein-allergic mice was measured. Flow cytometry was used to analyse the effects of linoleic acid on the proportion of ILC2s and the release of IL-5/IL-13. The PPARα agonist WY14643 and the NF-κB signalling pathway inhibitor MLN120B were used to study immune regulation, and transcriptomic sequencing was performed to elucidate the underlying molecular mechanism. RESULTS: Compared with control mice, allergic mice presented ILC2s with increased LA levels, increased proportions of ILC2s, and increased IL-5/IL-13 release. PPARα agonists reduced the proportion of ILC2s and decreased inflammation and allergic reactions. Transcriptomic analysis revealed that LA may activate the NF-κB signalling pathway; its inhibition reduced the proportions of ILC2s and the levels of cytokines in CMPA mice. CONCLUSION: Linoleic acid may regulate ILC2s via the NF-κB signalling pathway and thereby promote IL-5/IL-13 release and exacerbate inflammation in CMPA mice. Inhibition of LA enrichment or the NF-κB signalling pathway may be potential therapies for CMPA in early childhood.