Reprogrammierung von Makrophagen durch GDF-15: Auswirkungen auf die IL17RB-Expression und die Immuntoleranz
Lina Susana Silva Bermudez (Mannheim / DE), Jingxuan Xu (Mannheim / DE), Harald Klüter (Mannheim / DE), Julia Kzhyshkowska (Mannheim / DE)
Growth/differentiation factor 15 (GDF-15) is a multifunctional cytokine involved in immune tolerance that is elevated in stress conditions, correlating with disease severity and survival. The role of GDF-15 in macrophages and its effects on their transcriptome have been studied only to a limited extent. In this study, we identified the transcriptional program induced by recombinant human GDF-15 (rGDF15) on human macrophages in the presence or absence of lipopolysaccharide (LPS).
Human monocytes were isolated from buffy coats by CD14+ positive selection and differentiated into M0 (non-stimulated), M1 (IFN-γ stimulated), and M2 (IL-4 stimulated) macrophages for 6 days. On day 6, macrophages were pre-treated with 50 ng/mL rGDF-15 for 1 hour, followed by a 6-hour challenge with 100 ng/mL LPS.
Total RNA Seq revealed that rGDF15 altered the expression of 210 genes in M0 and of 372 in M2. rGDF15 and LPS in M0 and M2 exhibited changes in 230 and 295 genes, respectively. Gene Ontology analysis highlighted enrichment in blood vessel morphogenesis and angiogenesis pathways following rGDF-15 treatment in both M0 and M2. The top upregulated GO terms in M0 and M2 under rGDF-15 and LPS belonged to the TGF-β receptor and cytokine signaling pathways. Validation by RT-PCR and flow cytometry confirmed increased expression of IL17RB in macrophages, suggesting immunmodulatory effect mediated by rGDF-15 in macrophages.
These findings highlight the ability of GDF-15 to affect programming of human macrophages, promote angiogenesis, and modulate TGF-β signalling. GDF-15 pathway should be explored as a therapeutic option in disease states where uncontrolled inflammatory activation is present.
The authors declare no conflict of interest