2026/05/18 by Dana María Negretti-Borga, Mariana Pires Teixeira, Antonella Blanco +8 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · Immunology and Microbiology · #Sphingolipid Metabolism and Signaling #Spondyloarthritis Studies and Treatments #Psoriasis: Treatment and Pathogenesis
paper · doi:10.1530/joe-26-0081
openalex publication_date 2026/05/18 · openalex created_date 2026/05/19 · openalex updated_date 2026/07/27
We previously reported that triiodothyronine (T3) promotes maturation of dendritic cells (DCs) and enhances their ability to induce pro-inflammatory and cytotoxic T-cell responses through Akt signaling. However, the underlying mechanisms remain incompletely understood. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, is implicated under several pro-inflammatory conditions. Here, we investigated the role of sphingosine kinase 1 (SK1), S1P, and its receptors (S1PRs) in the immunomodulatory effects of T3 on DCs and the ensuing adaptive immune response. DCs were generated from the bone marrow of C57BL/6 wild-type or SK1 knockout mice and stimulated with T3 (T3-DC). To modulate the S1P pathway, PF-543 (SK1 inhibitor), S1P, or FTY720 (S1PR functional antagonist) was added prior to T3. Phosphorylated Akt (p-Akt) and phosphorylated STAT3 (p-STAT3) were analyzed by Western blotting. Splenocytes from BALB/c mice were co-cultured with DCs under SK1 or S1PR inhibition and exposed to T3. Cell markers and proliferation were evaluated by flow cytometry, and cytokines were measured by flow cytometry and ELISA. We show that the SK1/S1P/S1PR pathway regulates IL-12p70 production in T3-DC, while S1PRs also modulate IL-6 secretion. Mechanistically, S1P signaling mediates T3-induced Akt phosphorylation in DCs. STAT3 activation was observed in T3-DC and was not altered by inhibition of SK1 or S1PR. Although the SK1/S1P/S1PR axis did not alter T cell proliferation, S1PR inhibition increased IFN-γ, and inhibition of either SK1 or S1PRs enhanced IL-17 secretion by splenocytes. Altogether, these findings suggest that a complex sphingolipid-mediated signaling network modulates the immunostimulatory effects of T3 on DCs and the driven adaptive immunity.