D2.369 - Impaired Retinoic Acid Metabolism and Eotaxin Overexpression in Eosinophilic Chronic Rhinosinusitis: Insights into Pathophysiology and Therapeutic Potential of CRABP1 Targeting

Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease characterized by type 2 inflammation and excessive eosinophil infiltration, often accompanied by nasal polyps. Retinoic acid (RA), a key regulator of immune homeostasis, has been shown to exhibit localized reductions in concentration in the lesion sites of ECRS patients. However, the precise role of RA and the mechanisms underlying its dysregulated metabolism in ECRS remain unclear. This study aimed to investigate the role of RA in ECRS, particularly how dysregulated RA metabolism affects eotaxin (CCL11, CCL26) expression and eosinophil recruitment.

Single-cell RNA sequencing (scRNA-seq) was performed to compare gene expression profiles of fibroblasts from ECRS patients and healthy controls. Isolated nasal fibroblasts were treated with RA, IL-4, IL-13, or Dupilumab, and the expression of RA metabolism-related genes (STRA6, ALDH1A2, CRABP1 and CRABP2) and eotaxins (CCL11, CCL26) was analyzed using real-time PCR. CRABP1 knockdown via siRNA was performed to evaluate its role in RA metabolism and eotaxin production. Eosinophil recruitment was validated using a microfluidic chip assay.

RA treatment of IL-4- and IL-13-stimulated fibroblasts induced CRABP1 overexpression, resulting in dysregulated RA metabolism and excessive CCL11 and CCL26 secretion. These eotaxin levels were associated with increased eosinophil recruitment in the microfluidic chip assay. In contrast, CRABP1 knockdown normalized RA metabolism, reduced CCL11 and CCL26 expression, and mitigated eosinophil recruitment. Dupilumab partially suppressed CRABP1 overexpression and partially reduced eotaxin hypersecretion caused by dysregulated RA metabolism.

CRABP1 plays a pivotal role in dysregulated RA metabolism and eotaxin regulation in ECRS fibroblasts under Th2 cytokine stimulation. Targeting CRABP1 may restore RA metabolism and reduce eotaxin-mediated eosinophil infiltration, providing a promising therapeutic strategy for ECRS.