Investigation of Fascin1, a Marker of Mature Dendritic Cells, Reveals a New Role for IL-6 Signaling in CCR7-Mediated Chemotaxis

• Published in: The Journal of immunology (1950) 2021-08, Vol.207 (3), p.938-949
• Main Authors: Matsumura, Fumio, Polz, Robin, Singh, Sukhwinder, Matsumura, Aya, Scheller, Jürgen, Yamashiro, Shigeko
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Blocking - pharmacology; Antigens, Differentiation - genetics; Antigens, Differentiation - metabolism; Cell Differentiation; Cells, Cultured; Chemotaxis; Dendritic Cells - immunology; Gene Expression Regulation; Interleukin-6 - metabolism; Mice; Mice, Knockout; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Receptors, CCR7 - metabolism; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - immunology; Receptors, Interleukin-6 - metabolism; Receptors, Odorant - genetics; Receptors, Odorant - metabolism; Signal Transduction
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2000318

Migration of mature dendritic cells (DCs) to lymph nodes is critical for the initiation of adaptive immunity. CCR7, a G-protein-coupled receptor for CCL19/21 chemokines, is known to be essential for chemotaxis of mature DCs, but the molecular mechanism linking inflammation to chemotaxis remains unclear. We previously demonstrated that fascin1, an actin-bundling protein, increases chemotaxis of mature mouse DCs. In this article, we demonstrated that fascin1 enhanced IL-6 secretion and signaling of mature mouse DCs. Furthermore, we demonstrated that IL-6 signaling is required for chemotaxis. Blockage of IL-6 signaling in wild-type DCs with an anti-IL-6 receptor α (IL-6Rα) Ab inhibited chemotaxis toward CCL19. Likewise, knockout of IL-6Rα inhibited chemotaxis of bone marrow-derived DCs. The addition of soluble IL-6Rα and IL-6 rescued chemotaxis of IL-6Rα knockout bone marrow-derived DCs, underscoring the role of IL-6 signaling in chemotaxis. We found that IL-6 signaling is required for internalization of CCR7, the initial step of CCR7 recycling. CCR7 recycling is essential for CCR7-mediated chemotaxis, explaining why IL-6 signaling is required for chemotaxis of mature DCs. Our results have identified IL-6 signaling as a new regulatory pathway for CCR7/CCL19-mediated chemotaxis and suggest that rapid migration of mature DCs to lymph nodes depends on inflammation-associated IL-6 signaling.