PDE4D-CXCL13 axis in gland epithelial cells promotes B cell infiltration in primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder characterized by immune cell, particularly B cell, infiltration into exocrine glands, where autoantibody production disrupts glandular architecture and secretory function. Unraveling the mechanisms that drive this B cell trafficking could unveil innovative therapeutic avenues for pSS. We report that phosphodiesterase 4D (PDE4D) is markedly up-regulated in glandular epithelial cells from both pSS patients and murine models, correlating tightly with diminished saliva output and heightened B cell infiltration. Mechanistically, lipopolysaccharide (LPS) engages Toll-like receptor 2/4 signaling in human salivary gland epithelial cells to induce PDE4D expression. Then, PDE4D reduces the phosphorylation of FOXO1 and enhances its nuclear translocation and stability; in turn, FOXO1 amplifies C-X-C motif chemokine ligand 13 (CXCL13) secretion that promotes B cell chemotaxis. To interrogate the functional relevance of PDE4D, we generated pSS models in PDE4D-knockout and wild-type (WT) mice, and additionally treated WT-pSS mice with a selective PDE4D inhibitor. Genetic deletion or pharmacologic inhibition of PDE4D augmented PKA-mediated FOXO1 phosphorylation, suppressed CXCL13 expression in glandular epithelial cells, and significantly attenuated disease manifestations. Collectively, our findings position PDE4D as a promising therapeutic target for pSS.