Elovanoids Counteract Inflammatory Signaling, Autophagy, Endoplasmic Reticulum Stress, and Senescence Gene Programming in Human Nasal Epithelial Cells Exposed to Allergens

Abstract

To contribute to further understanding the cellular and molecular complexities of inflammatory-immune responses in allergic disorders, we have tested the pro-homeostatic elovanoids (ELV) in human nasal epithelial cells (HNEpC) in culture challenged by several allergens. ELV are novel bioactive lipid mediators synthesized from the omega-3 very-long-chain polyunsaturated fatty acids (VLC-PUFA,n-3). We ask if: (a) several critical signaling events that sustain the integrity of the human nasal epithelium and other organ barriers are perturbed by house dust mites (HDM) and other allergens, and (b) if ELV would participate in beneficially modulating these events. HDM is a prevalent indoor allergen that frequently causes allergic respiratory diseases, including allergic rhinitis and allergic asthma, in HDM-sensitized individuals. Our study used HNEpC as an in vitro model to study the effects of ELV in counteracting HDM sensitization resulting in inflammation, endoplasmic reticulum (ER) stress, autophagy, and senescence. HNEpC were challenged with the following allergy inducers: LPS, poly(I:C), or Dermatophagoides farinae plus Dermatophagoides pteronyssinus extract (HDM) (30 µg/mL), with either phosphate-buffered saline (PBS) (vehicle) or ELVN-34 (500 nM). Results show that ELVN-34 promotes cell viability and reduces cytotoxicity upon HDM sensitization of HNEpC. This lipid mediator remarkably reduces the abundance of pro-inflammatory cytokines and chemokines IL-1β, IL-8, VEGF, IL-6, CXCL1, CCL2, and cell adhesion molecule ICAM1 and restores the levels of the pleiotropic anti-inflammatory IL-10. ELVN-34 also lessens the expression of senescence gene programming as well as of gene transcription engaged in pro-inflammatory responses. Our data also uncovered that HDM triggered the expression of key genes that drive autophagy, unfolded protein response (UPR), and matrix metalloproteinases (MMP). ELVN-34 has been shown to counteract these effects effectively. Together, our data reveal a novel, pro-homeostatic, cell-protective lipid-signaling mechanism in HNEpC as potential therapeutic targets for allergies.

IL-1β and Allergy: Focusing on Its Role in Allergic Rhinitis

“…In addition, some epithelial cells previously thought not to produce cytokines [54], such as epithelial cells in the respiratory tract, epidermis, and digestive tract, have also been reported to release IL-1β in allergic diseases [55,56]. It was also found that nasal mucosal epithelial cells produced IL-1β after being stimulated by allergens [57], which was consistent with the findings in in vitro human nasal mucosa epithelial cell models exposed to allergen or in in vivo AR animal models [58,59]. Therefore, how to precisely regulate IL-1β in the AR nasal mucosal epithelium has become a hot research topic.…”

Oral immunotherapy with enteric-coated capsules for allergic rhinitis caused by house dust mites

“…It has shown that in administering HDMs OIT, the oral route does not seem to offer a superior efficacy over the conventional routes; this conflict may be attributed to patient selection and allergen bioavailability to the gut due to gastric enzymatic degradation ( 9 , 10 ). HDMs are a prevalent indoor allergen causing allergic respiratory diseases, including AR and allergic asthma ( 11 ). The objective of this study is to verify a hypothesis that Dermatophagoides farina ( Df ) encapsulated in enteric-coated capsules might effectively treat HDMs-induced AR through OIT, achieving a similar or superior effect to that of SCIT.…”