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

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.

Livin promotes Th2-type immune response in airway allergic diseases

“…Interestingly, Xue et al newly discovered that livin played a critical role in ECRSwNP. Livin facilities nasal chronic inflammation by promoting the thymic stromal lymphopoietin (TSLP) expression in nasal epithelial cells [26]. Apparently, it is different with conclusion as described previously.…”

Association between glucocorticoid receptor beta and steroid resistance: A systematic review

“…Choi and colleagues revealed that the GC‐resistant group had a higher level of GR‐α than the sensitive group 18 . However, Xue and colleagues observed a decreased GR‐α in the resistant group 16 . Additionally, Li and colleagues reported that the ratio of GR‐α/GR‐β was lower in the GC‐resistant group compared to the sensitive group 17 …”

“…18 However, Xue and colleagues observed a decreased GR-α in the resistant group. 16 Additionally, Li and colleagues reported that the ratio of GR-α/GR-β was lower in the GC-resistant group compared to the sensitive group. 17…”

The transcription factor XBP1 in dendritic cells promotes the T H 2 cell response in airway allergy

“…Here, we found that upon exposure to PM2.5, RAS activation was enhanced in DCs, which was abolished by the depletion of SOS1, consistent with previous reports ( 13 ). Aberrant RAS activation is one of the factors that skews cellular activities, for example, the uncontrolled growth of cancers ( 13 ), the sustained production of thymic stromal lymphopoietin (TSLP) by airway epithelial cells of patients with allergic rhinitis ( 34 ), and the overexpression of Twist-1 protein in the neutrophils of patients with ulcerative colitis to induce corticosteroid resistance ( 35 ). We observed the increased abundance of TIM4 in the DCs of patients with allergies, as was reported previously ( 3 , 4 ).…”