Inhibition of miR-99a-5p prevents allergen-driven airway exacerbations without compromising type-2 memory responses in the intestine following helminth infection

Abstract

Acute exacerbations (AE) of asthma, remain one of the biggest concerns for patients living with asthma. As such, identifying the causes, the molecular mechanisms involved and new therapeutic interventions to prevent AE is a high priority. Immunity to intestinal helminths involves the reactivation of type-2 immune responses leading to smooth muscle contraction and mucus hypersecretion–physiological processes very similar to acute exacerbations in the airways following allergen exposure. In this study, we employed a murine model of intestinal helminth infection, using Heligmosomoides polygyrus, to identify miRNAs during active expulsion, as a system for the identification of miRNAs that may contribute to AE in the airways. Concomitant with type-2 immunity and expulsion of H. polygyrus, we identified miR-99a-5p, miR-148a-3p and miR-155-5p that were differentially regulated. Systemic inhibition of these miRNAs, alone or in combination, had minimal impact on expulsion of H. polygyrus, but inhibition of miR-99a-5p or miR-155-5p significantly reduced house dust mite (HDM)-driven acute inflammation, modelling human acute exacerbations. Immunological, pathological and transcriptional analysis identified that miR-155-5p or miR-99a-5p contribute significantly to HDM-driven AE and that transient inhibition of these miRNAs may provide relief from allergen-driven AE, without compromising anti-helminth immunity in the gut.

Exploration of the Molecular Mechanisms of Hyssopus cuspidatus Boriss Treatment of Asthma in an mRNA-miRNA Network via Bioinformatics Analysis

“…8-Hydroxycirsimaritin and methyl rosmarinate interacted with 21 miRNAs, regulating inflammation and apoptosis by targeting PIK3CB, MAPK1, STAT3, EGFR, and AKT (according to the topological parameters). In total, 15 compounds, including caffeic acid, luteolin, esculetin, chrysin, and methyl rosmarinate, cooperatively interacted with miR-99a, contributing to NF- κ B-induced inflammatory cytokine production, T-cell activation, and allergen-driven exacerbations of airway disease [ 59 – 61 ]. Notably, maslinic acid and 20 β -hydroxyursolic acid interact with the same binding miRNAs (miR-33b, miR-18a, miR-99a, and miR-328) and mRNA targets (ESR1 and PTPN6).…”

circ_0075943 Dominates the miR-141-3p/AK2 Network to Support the Development of Breast Carcinoma

“…MiRNAs constitute a class of small single-stranded noncoding RNA, and thousands of miRNAs are believed to be involved in metabolism, signal transduction, cell adhesion, cell motility, cell differentiation, and apoptosis [ 20 – 22 ]. Therefore, for different earmark genes and cancer types, miRNAs have been observed to be both oncogenes and tumor suppressors [ 23 ].…”

miR-99a-5p: A Potential New Therapy for Atherosclerosis by Targeting mTOR and Then Inhibiting NLRP3 Inflammasome Activation and Promoting Macrophage Autophagy

“…In addition, increasing attention to the cause of the above trend should be paid. Several previous studies have revealed that the expression level of miR-99a-5p might be related to inflammation and immune responses [38][39][40]. Since AS was a chronic inflammatory disease [41,42], we then explored whether miR-99a-5p could affect inflammatory cytokines.…”