Impaired retinoic acid metabolism and eotaxin overexpression in eosinophilic chronic rhinosinusitis: Insights into pathophysiology and therapeutic potential of CRABP1 targeting

초록

Background: Eosinophilic chronic rhinosinusitis (ECRS) is achronic inflammatory disease characterized by type 2 inflam-mation and excessive eosinophil infiltration, often accompaniedby nasal polyps. Retinoic acid (RA), a key regulator of immunehomeostasis, has been shown to exhibit localized reductions inconcentration in the lesion sites of ECRS patients. However, theprecise role of RA and the mechanisms underlying its dysreg-ulated metabolism in ECRS remain unclear. This study aimedto investigate the role of RA in ECRS, particularly how dysreg-ulated RA metabolism affects eotaxin (CCL11, CCL26) expres-sion and eosinophil recruitment.Method: Single- cell RNA sequencing (scRNA- seq) was per -formed to compare gene expression profiles of fibroblasts fromECRS patients and healthy controls. Isolated nasal fibroblastswere treated with RA, IL- 4, IL-13, or Dupilumab, and the ex-pression of RA metabolism-related genes (STRA6, ALDH1A2,CRABP1 and CRABP2) and eotaxins (CCL11, CCL26) was ana-lyzed using real-time PCR. CRABP1 knockdown via siRNA wasperformed to evaluate its role in RA metabolism and eotaxinproduction. Eosinophil recruitment was validated using a mi-crofluidic chip assay.Results: RA treatment of IL- 4- and IL-13-stimulated fibroblastsinduced CRABP1 overexpression, resulting in dysregulated RAmetabolism and excessive CCL11 and CCL26 secretion. Theseeotaxin levels were associated with increased eosinophil re-cruitment in the microfluidic chip assay. In contrast, CRABP1knockdown normalized RA metabolism, reduced CCL11 andCCL26 expression, and mitigated eosinophil recruitment.Dupilumab partially suppressed CRABP1 overexpression andpartially reduced eotaxin hypersecretion caused by dysregu-lated RA metabolism.Conclusion: CRABP1 plays a pivotal role in dysregulated RAmetabolism and eotaxin regulation in ECRS fibroblasts underTh2 cytokine stimulation. Targeting CRABP1 may restore RAmetabolism and reduce eotaxin-mediated eosinophil infiltra-tion, providing a promising therapeutic strategy for ECRS.Conflicts of Interest: no conflict of interest