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. 2009 Mar 19:10:14.
doi: 10.1186/1471-2172-10-14.

Interferon-gamma coordinates CCL3-mediated neutrophil recruitment in vivo

Cynthia A Bonville  1 , Caroline M Percopo, Kimberly D Dyer, Jiliang Gao, Calman Prussin, Barbara Foster, Helene F Rosenberg, Joseph B Domachowske
Affiliations

Interferon-gamma coordinates CCL3-mediated neutrophil recruitment in vivo

Cynthia A Bonville et al. BMC Immunol. .

Abstract

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 (IFNgamma). Neutrophil recruitment in response to PVM infection was diminished five-fold in IFNgamma receptor gene-deleted mice, although neutrophils from IFNgammaR -/- 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 IFNgamma. Interestingly, although supplemental IFNgamma restored neutrophil recruitment and resulted in a sustained weight loss among CCL3-overexpressing IFNgamma -/- 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 IFNgamma and CCL3, which demonstrate that IFNgamma is crucial for CCL3-mediated neutrophil recruitment in vivo.

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Figures

Figure 1
Figure 1
(A) Expression of transcripts in mouse lung tissue in response to PVM infection: IFN-γ and IFN-γ correlating profiles. Baseline expression in uninfected mice (day 0) is set at 1.0 and normalized expression (per gene, per chip) is shown for days 1 – 7, 10, 14, 21 and 28 after inoculation. Profiles of 203 transcripts with patterns that correlate with that the profile of IFN-γ (0.900 to 0.969) are shown in yellow to red, respectively, and identified by name in Table 1. The expression profile of CCL3 (MIP-1α), a chemokine crucial for neutrophil recruitment in response to PVM infection, is overdrawn with a blue line (correlation 0.965). (B) Correlation of IFN-γ and CCL3 protein levels in individual PVM-infected mice. IFN-γ and CCL3 detected by ELISA in lung tissue homogenates from individual mice days 0 – 28 after inoculation with 30 pfu PVM (n = 43) are as shown. (C) IFNγ+ NK and T cells detected in lungs of PVM-infected mice. Total and IFNγ+ NK cells, CD4+ T cells, and CD8+ T cells (± sd) detected per lung on day 6 after inoculation with 10 pfu PVM.
Figure 2
Figure 2
Neutrophil recruitment in response to PVM infection is diminished in IFN-γR gene-deleted mice. (A) Neutrophils detected in BAL fluid 5 days after inoculation; hpf, high power field; *p < 0.001;(B) Detection of CCL3 in BAL fluid; *p < 0.001 (C) Virus copy number detected in lung tissue determined by quantitative RT-PCR.
Figure 3
Figure 3
Comparison of wild type and IFNγR gene-deleted neutrophils. (A) Expression of CCR1 transcript in wild type and IFNγR gene-deleted neutrophils (n = 9 and 6 independent samples, respectively) determined by quantitative RT-PCR; horizontal line denotes mean copy number. (B) Calcium flux (RFU) measured in response to increasing concentrations (0 – 500 nM) of CCL3.
Figure 4
Figure 4
Heterologous expression of CCL3 in mouse lungs. (A) Detection of immunoreactive CCL3 in lungs of mice on day 9 after challenge via intranasal inoculation with the CCL3 overexpression vector (vCCL3) or control vector (vctrl), *p < 0.01. (B) Lung tissue from mice challenged with vCCL3, immunohistochemical localization of CCL3 within bronchiolar epithelial cells (at arrows), (C) Lung tissue from mice challenged with vctrl.
Figure 5
Figure 5
Neutrophil recruitment in response to CCL3 is ablated in IFN-γ gene-deleted mice. (A) Neutrophils detected in BAL fluid of IFNγ gene-deleted (IFNγ -/-) mice (+vctrl +med (medium; RPMI + 10% FCS vehicle control); open bar), + IFNγ (+vctrl + IFNγ, grey-shaded bar), +vCCL3 +med (black bar), or +vCCL3 + IFNγ (black-shaded bar); *p < 0.01 vs. other conditions, day 9 after challenge with vCCL3 or vctrl. (B, C) Microscopic images of lung tissue from IFN-γ -/- mice challenged with (B) vCCL3 + med or (C) vCCL3 + IFNγ; original magnification, 20×. Inset, original magnification 63×, documenting neutrophil recruitment. (D) Change in body weight in response to CCL3 overexpression ± IFN-γ; *p < 0.01 at time points shown.
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