Apolipoprotein E promoted the proliferation and function of group 2 innate lymphoid cells through low density lipoprotein receptor in allergic rhinitis.

Abstract

Background: Apolipoprotein E (ApoE) promoted neutrophilic airway inflammation in mice with allergic asthma. Although group 2 innate lymphoid cells (ILC2s) have been established as pivotal mediators in allergic rhinitis (AR) pathogenesis, endogenous mechanisms regulating their hyperactivity are undefined. Whether ApoE has effects in ILC2s in AR is still unknown.

Objective: The aim of this investigation is to identify the crucial function of the suppressor modulator ApoE in regulating ILC2-mediated allergic airway inflammation.

Methods: A cohort comprising 15 pediatric AR patients and matched healthy controls was enrolled to assess serum ApoE messenger RNA (mRNA) expression and protein levels and their relationship with interleukin (IL)-5, IL-13 and total nasal symptoms scores (TNSS). In vitro experiments employing flow cytometry and enzyme-linked immunosorbent assay (ELISA) validated the regulatory effects of ApoE on ILC2s expansion capacity and cytokine secretion. Transcript levels of GATA binding protein 3 (GATA3) and retinoid acid receptor related orphan receptor alpha (RORα) was examined using quantitative reverse transcription polymerase chain reaction (qRT-RCR). The changes of IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) levels after stimulation of human nasal epithelial cells (HNECs) by Dermatophagoides pteronyssinus (Der p), ApoE and anti-Low-Density Lipoprotein Receptor (LDLR) were determined by ELISA. The effects of ApoE and anti-LDLR in vivo were using the ovalbumin (OVA)-induced murine model.

Results: Clinical analyses indicated elevated serum ApoE mRNA and protein levels in AR patients, positively correlating with TNSS. Recombinant ApoE effectively promoted ILC2 activation in PBMCs from AR patients, inducing GATA3 and RORα expression and IL-5, IL-13 secretion, while these effects of ApoE were eliminated by anti-LDLR. Mechanistically, ApoE augmented the epithelial-ILC2 crosstalk by inducing nasal epithelial TSLP/IL-25/IL-33 release. Additionally, our studies have revealed that the anti-LDLR effectively reversed the effects of ApoE on those cytokine production. In vivo, administering anti-LDLR to AR mice effectively alleviates OVA and ApoE induced allergic airway inflammation, reducing eosinophilic infiltration and nasal symptoms, as well as OVA specific immunoglobulin E (IgE) and ILC2 proliferation.

Conclusions: As our findings demonstrate, targeting the ApoE-LDLR axis has considerable therapeutic promise in treating ILC2-dependent allergic airway inflammation.