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.
Highlights
The challenge to effectively manage allergic rhinitis, asthma, and other allergic conditions is due in part to our limited understanding of the mechanisms involved
Because LCPUFAs have been shown to play an important role in the control of mediators involved in inflammation, exerting a protective role of cellular integrity against inflammation [6,7,8,21,22], we proposed to determine whether ELV could be useful to protect human nasal epithelial cells (HNEpC) exposed to House dust mites (HDM)-induced deleterious actions
To test the efficacy of ELV on cell survival, HNEpC were challenged with different stressors/allergy inducers—lipopolysaccharide (LPS), poly(I:C), or house dust mite extracts (HDM) (30 μg/mL) and, 30 min later, the cells were treated with ELVN-34 (500 nM) and incubated for 24 h
Summary
The challenge to effectively manage allergic rhinitis, asthma, and other allergic conditions is due in part to our limited understanding of the mechanisms involved. Elovanoids (ELV) are bioactive lipid mediators derived from very-long-chain polyunsaturated fatty acids (VLC-PUFA,n-3), which are the biosynthetic products of the newly discovered elongase ELOVL4 (Figure S1) These novel lipid mediators are able to downregulate senescence gene programming, senescence-associated secretory phenotype (SASP), and inflammaging (age-dependent, low-grade, chronic inflammation), which in turn promotes and sustains cell structural integrity, viability, and function [16,17,18,19,20]. The inflammaging is partly attributable to dysregulated immune systems leading to the development of the SASP program that consists of the release of multiple cytokines, chemokines, and mitokines by the accumulation of senescent non-immune tissue cells with a pro-inflammatory effect [29] This dysregulation has been associated with environmental allergens or pollutants in the SASP program and in the processes of autophagy and mitophagy [30]. The results obtained from this study will make it possible to determine a new pro-homeostatic and cell-protective lipid signaling mechanism in nasal epithelial cells with the aim of selecting new potential therapeutic targets for the treatment of allergies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
