MUC4 overexpression correlates corticoid resistance in chronic rhinosinusitis with nasal polyps

Background: Some patients with chronic rhinosinusitis with nasal polyps (CRSwNP) are resistant to corticoids. Mucin 4 (MUC4) is a membrane anchored protein with a nuclear translocation domain which is modulated by corticoids. Because glucocorticoid receptor (GR) nuclear translocation is key to the anti-inflammatory effect of corticoids, we hypothesized that MUC4 is involved in the effectiveness of these drugs Objective: To analyze the role of MUC4 in corticoid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved Methods: 73 patients with CRSwNP took oral corticoids for 15 days. Corticoid resistance was evaluated by nasal endoscopy. The expression of MUC4 was determined by real-time PCR, Western blotting, and immunohistochemistry. Beas-2B knockdown with RNA interference for MUC4 (siRNA-MUC4) was used to analyze the role of MUC4 in the anti-inflammatory effects of dexamethasone Results: 90 patients had nasal polyps with corticoid resistance (NP-CR). MUC4 expression was upregulated in these patients. Primary epithelial cells from NP-CR were insensitive to the anti-inflammatory effects of dexamethasone. In siRNA-MUC4 Beas-2B, dexamethasone showed higher anti-inflammatory effects. Immunoprecipitation revealed that MUC4 and GRα form protein complexes modulated by dexamethasone. In epithelial cells from NP-CR MUC4-GRα complex is not dissociated in presence of dexamethasone, avoiding the GRα nuclear translocation and therefore its anti-inflammatory effects Conclusion: MUC4 participates in the corticoid response that mediates GRα nuclear translocation. The high expression of MUC4 in patients with CRSwNP may participate in corticoid resistance.