Vitamin D receptor drives macrophage M2 polarization and exacerbates airway inflammation in asthma

Asthma is a chronic inflammatory airway disease characterized by epithelial barrier dysfunction, mucus hypersecretion, and type 2-skewed immune responses. Macrophages play a critical role in shaping airway inflammation and tissue remodeling, yet the molecular mechanisms regulating macrophage activation in allergic asthma remain incompletely understood. The vitamin D receptor (VDR) is an immune-modulatory transcription factor expressed in macrophages, but its macrophage-specific function and regulatory mechanisms in allergic airway inflammation remain unclear.

We investigated the role of macrophage VDR signaling using a chronic house dust mite (HDM)-induced asthma model combined with myeloid-specific Vdr conditional knockout mice. Airway inflammation, epithelial remodeling, and macrophage polarization were assessed by histological, molecular, and flow cytometric analyses. Mechanistic studies were performed to identify nuclear localization sequences (NLSs) of VDR and to evaluate their interaction with the nuclear import adaptor KPNA1.

HDM exposure increased VDR expression in macrophages both in vivo and in vitro. Myeloid-specific deletion of Vdr significantly attenuated airway inflammation, reduced inflammatory cell recruitment, and alleviated epithelial barrier disruption and mucus metaplasia. Mechanistically, VDR promoted macrophage M2-like polarization in response to HDM stimulation. We further identified a previously unrecognized C-terminal nuclear localization sequence spanning amino acids 387-412 that is required for VDR nuclear translocation and macrophage polarization. Structural modeling and biochemical analyses indicated that phosphorylation within this region enhances the interaction between VDR and the nuclear import adaptor KPNA1, thereby facilitating nuclear import of VDR.

These findings identify macrophage-intrinsic VDR signaling as an important regulator of allergic airway inflammation and reveal a phosphorylation-dependent mechanism controlling VDR nuclear trafficking and macrophage polarization.