Int J Biol Sci 2021; 17(8):2089-2098. doi:10.7150/ijbs.58427

Research Paper

Livin in synergy with Ras induces and sustains corticosteroid resistance in the airway mucosa

Jin-Mei Xue1*, Yun-Fang An1*, Li-Min Suo1*, Li-Hua Mo2,3, Gui Yang4, Xiang-Qian Luo5, Da-Bo Liu5, Chang-Qing Zhao1✉, Ping-Chang Yang2,3✉

1. Department of Otolaryngology, Head & Neck Surgery, Second Hospital, Shanxi Medical University, Taiyuan, China.
2. Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China.
3. Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.
4. Department of Otolaryngology, Longgang Central Hospital, Shenzhen, China.
5. Department of Pediatric Otolaryngology, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
*These authors equally contributed to this work.

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Citation:
Xue JM, An YF, Suo LM, Mo LH, Yang G, Luo XQ, Liu DB, Zhao CQ, Yang PC. Livin in synergy with Ras induces and sustains corticosteroid resistance in the airway mucosa. Int J Biol Sci 2021; 17(8):2089-2098. doi:10.7150/ijbs.58427. Available from https://www.ijbs.com/v17p2089.htm

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Abstract

Rationale: Corticosteroid resistance (CR) seriously affects the therapeutic effects of steroids on many chronic inflammatory disorders, including airway allergy. The mechanism of CR development is unclear. Recent research indicates that livin, an apoptosis inhibitor, is associated with the regulation in cell activities. This study investigates the role of livin in the inducing and sustaining CR in the airway mucosa.

Methods: Nasal epithelial cells (NECs) were isolated from surgically removed nasal mucosal tissues of patients with allergic rhinitis (AR) and nasal polyps with or without CR. Differentially expressed genes in NECs were analyzed by the RNA sequencing. A CR mouse model was developed to test the role of livin in CR development.

Results: The results showed that NECs of AR patients with CR expressed high levels of livin, that was positively correlated with the thymic stromal lymphopoietin (TSLP) expression and the high Ras activation status in NECs. Livin and Ras activation mutually potentiating each other in the inducing and sustaining the TSLP expression in NECs. TSLP induced eosinophils and neutrophils to express glucocorticoid receptor-β (GRβ). Eosinophils and neutrophils with high CRβ expression were resistant to corticosteroids. Depletion of livin or inhibition of TSLP markedly attenuated CR and airway allergy.

Conclusions: Livin facilitates CR development in the airways by promoting TSLP expression in epithelial cells and the GRβ expression in eosinophils and neutrophils. Depletion of livin or inhibiting TSLP attenuates CR development and inhibits airway allergy, this has the translational potential to be used in the treatment of airway allergy.

Keywords: nasal mucosa, epithelial cell, inflammation, corticosteroid resistance, glucocorticoid receptor, livin