IL‐15 mediates antigen‐induced neutrophil migration by triggering IL‐18 production

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Abstract
We have investigated the mechanisms underlying IL‐15‐induced neutrophil migration into inflamed tissues. IL‐15 induced neutrophil migration to the peritoneal cavity in mice in a time‐ and dose‐dependent manner. The cell migration was not induced in IL‐18–/–, MIP‐1α (CCL3)–/–, TNFR1–/– or 5‐LOX–/– mice but was normal in IFN‐γ–/– mice. IL‐15‐induced neutrophil migration was inhibited by anti‐MIP‐2 (CXCL2) antibody or MK886 (leukotriene synthesis inhibitor). IL‐18‐induced neutrophil migration was also dependent on TNFR1, MIP‐1α, MIP‐2 and leukotriene. Consistent with this observation, IL‐15 induced IL‐18 production, and IL‐15 or IL‐18 injection induced the production of MIP‐2, MIP‐1α, TNF‐α and LTB4. In an antigen‐specific inflammation model, ovalbumin (OVA)‐induced neutrophil migration was completely inhibited by soluble IL‐15Rα (sIL‐15Rα) or anti‐MIP‐2 antibody. Furthermore, cell migration was absent in IL‐18–/–, MIP‐1α–/–, TNFR1–/–, or 5‐LOX–/– mice. OVA challenge induced the release of MIP‐2, MIP‐1α, TNF‐α and LTB4 in the peritoneal cavity in an IL‐15‐ and IL‐18‐dependent manner. We also found that neutrophils from the peripheral blood and synovial fluid of patients with rheumatoid arthritis produced substantial amounts of IL‐18 and LTB4 following activation by IL‐15. Together, these results demonstrate that IL‐15 plays an important role in antigen‐induced neutrophil migration during inflammation, triggering a sequential OVA, IL‐15, IL‐18, MIP‐2, MIP‐1α, TNF‐α, LTB4 and neutrophil migration signaling cascade.

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