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

Waldiceu A Verri1, Thiago M Cunha, Sérgio H Ferreira

  • 1Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

European Journal of Immunology
|November 6, 2007
PubMed

Insights

Interleukin-15 (IL-15) drives neutrophil migration to inflamed tissues via a pathway involving IL-18, chemokines like MIP-2, and leukotrienes. This IL-15 signaling cascade is crucial for antigen-induced inflammation.

Area of Science:

  • Immunology
  • Inflammation research
  • Cellular signaling

Background:

  • Neutrophil migration is critical in inflammatory responses.
  • Interleukin-15 (IL-15) is implicated in immune cell trafficking.
  • Understanding the precise mechanisms of IL-15-mediated neutrophil recruitment is essential.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which IL-15 induces neutrophil migration into inflamed tissues.
  • To identify key signaling molecules and pathways involved in IL-15-driven neutrophil recruitment.
  • To investigate the role of IL-15 in antigen-specific inflammatory models and rheumatoid arthritis.

Main Methods:

  • Utilized mouse models with genetic deficiencies (IL-18-/-, MIP-1alpha-/-, TNFR1-/-, 5-LOX-/-) to assess neutrophil migration.
  • Employed antibodies (anti-MIP-2) and inhibitors (MK886) to block specific molecular pathways.
  • Analyzed cytokine and chemokine production (IL-18, MIP-2, MIP-1alpha, TNF-alpha, LTB4) in response to IL-15 and IL-18 stimulation.
  • Investigated neutrophil function in patients with rheumatoid arthritis.

Main Results:

  • IL-15 induced dose- and time-dependent neutrophil migration to the peritoneal cavity in wild-type mice.
  • Neutrophil migration was dependent on IL-18, MIP-1alpha (CCL3), TNFR1, and 5-lipoxygenase (5-LOX), but not IFN-gamma.
  • IL-15-induced migration was inhibited by anti-MIP-2 (CXCL2) antibody and a leukotriene synthesis inhibitor (MK886).
  • IL-15 triggered a cascade: IL-15 -> IL-18 production -> MIP-2, MIP-1alpha, TNF-alpha, LTB4 production -> neutrophil migration.
  • Antigen (ovalbumin)-induced neutrophil migration was abrogated in IL-18-/-, MIP-1alpha-/-, TNFR1-/-, or 5-LOX-/- mice and inhibited by sIL-15Ralpha or anti-MIP-2.
  • Neutrophils from rheumatoid arthritis patients produced IL-18 and LTB4 upon IL-15 activation.

Conclusions:

  • IL-15 is a key mediator of antigen-induced neutrophil migration in inflammation.
  • The pathway involves a sequential activation of IL-15, IL-18, chemokines (MIP-2, MIP-1alpha), TNF-alpha, and leukotrienes (LTB4).
  • This IL-15-driven signaling cascade represents a potential therapeutic target for inflammatory diseases.

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