Interferon-gamma coordinates CCL3-mediated neutrophil recruitment in vivo

Background: We have shown previously that acute infection with the respiratory pathogen, pneumonia virus of mice (PVM), results in local production of the proinflammatory chemokine, CCL3, and that neutrophil recruitment in response to PVM infection is reduced dramatically in CCL3 -/- mice. Results: In this work, we demonstrate that CCL3-mediated neutrophil recruitment is coordinated by interferon-gamma (IFN gamma). Neutrophil recruitment in response to PVM infection was diminished five-fold in IFN gamma receptor gene-deleted mice, although neutrophils from IFN gamma R -/- mice expressed transcripts for the CCL3 receptor, CCR1 and responded functionally to CCL3 ex vivo. Similarly, in the absence of PVM infection, CCL3 overexpression alone could not elicit neutrophil recruitment in the absence of IFN gamma. Interestingly, although supplemental IFN gamma restored neutrophil recruitment and resulted in a sustained weight loss among CCL3-overexpressing IFN gamma -/- mice, CCL3-mediated neutrophil recruitment alone did not result in the pulmonary edema or respiratory failure characteristic of severe viral infection, suggesting that CCL3 and IFN-gamma together are sufficient to promote neutrophil recruitment but not pathologic activation. Conclusion: Our findings reveal a heretofore unrecognized hierarchical interaction between the IFN gamma and CCL3, which demonstrate that IFN gamma is crucial for CCL3-mediated neutrophil recruitment in vivo.