Stage-dependent association of Vitamin D receptor with macrophage polarization in allergic rhinitis

Background: Allergic rhinitis (AR) is driven by Th1/Th2 imbalance, with macrophages as key mediators. Vitamin D (VitD) deficiency is associated with AR; however, how VitD regulates macrophage-related molecules remains unclear.

Objective: This study investigated stage-specific effects of VitD receptor (VDR) signaling on macrophage-related molecules and immune responses in an ovalbumin (OVA)-induced AR rat model.

Methods: Beginning in the sensitization phase, rats received either the VDR agonist paricalcitol or the antagonist ZK168281. Outcomes were assessed during sensitization, re-challenge, and chronic maintenance phases, including nasal symptoms, nasal mucosal histopathology, serum OVA-specific IgE and M1/M2-like macrophage associated cytokines, spleen-derived cell transcriptomics, and nasal immunofluorescence for NOS2/ARG1 (M1/M2-like markers).

Results: Our findings demonstrate that VDR activation conferred maximal protection during the re-challenge phase, characterized by alleviated nasal symptoms, attenuated epithelial injury and inflammatory infiltration, and reduced OVA-specific IgE levels. Transcriptomic analysis revealed stage-dependent association of macrophage polarization: VDR signaling promoted the expression of M2-like-associated genes (e.g., Arg1, CD163, and Mertk) during sensitization and chronic maintenance while suppressing M1-like inflammatory mediators and chemokines (e.g., Il6, Il1β, CXCL9/10, and Ccl2) during re-challenge. These findings were corroborated at the protein level, with the serum cytokine analysis showing suppression of M1-like associated IL-6 and TNF-α, and nasal mucosal immunofluorescence confirming consistent and marked ARG1 expression upregulation.

Conclusion: VDR signaling is associated with stage-dependent immunomodulation in AR, promoting M2-like molecules expression during sensitization and suppressing M1 like driven inflammation during re-challenge, thereby weakening effects in the chronic phase. These findings support a "chronotherapeutic" application of VitD in AR.