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Interferon-gamma coordinates CCL3-mediated neutrophil recruitment in vivo.

Bonville CA, Percopo CM, Dyer KD, Gao J, Prussin C, Foster B, Rosenberg HF, Domachowske JB - BMC Immunol. (2009)

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: SUNY Upstate Medical University, Syracuse, New York 13210, USA. bonvillc@upstate.edu

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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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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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.

Mentions: We examined neutrophil recruitment in response to CCL3 overexpression in IFNγ gene-deleted mice (IFNγ -/-) with and without IFNγ supplementation. As shown in Figure 5A, few neutrophils are detected in BAL fluid at baseline (vctrl) and no recruitment over baseline is observed in response to IFNγ alone. Likewise, overexpression of CCL3 in the absence of IFNγ does not elicit neutrophil recruitment. Neutrophil recruitment (~10 – fold over baseline) was observed in response to CCL3 expression only in the presence of IFNγ. At the microscopic level, no inflammation was observed in lung tissue of IFNγ -/- mice in response to CCL3 overexpression alone [Figure 5B]. In contrast, significant pathology was observed in lung tissue of IFNγ -/- mice expressing CCL3 and supplemented with exogenous IFNγ. Findings include moderate peribronchiolar granulocytic infiltration and substantial parenchymal involvement but minimal edema fluid within the bronchioles and in the parenchymal tissue [Figure 5C]. Interestingly, weight loss is sustained among the mice overexpressing CCL3 while receiving supplemental IFNγ over the 9 day examination period [Figure 5D], but, despite the substantial inflammatory response, we observe no progression to respiratory failure up to and including t = 14 days.


Interferon-gamma coordinates CCL3-mediated neutrophil recruitment in vivo.

Bonville CA, Percopo CM, Dyer KD, Gao J, Prussin C, Foster B, Rosenberg HF, Domachowske JB - BMC Immunol. (2009)

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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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.
Mentions: We examined neutrophil recruitment in response to CCL3 overexpression in IFNγ gene-deleted mice (IFNγ -/-) with and without IFNγ supplementation. As shown in Figure 5A, few neutrophils are detected in BAL fluid at baseline (vctrl) and no recruitment over baseline is observed in response to IFNγ alone. Likewise, overexpression of CCL3 in the absence of IFNγ does not elicit neutrophil recruitment. Neutrophil recruitment (~10 – fold over baseline) was observed in response to CCL3 expression only in the presence of IFNγ. At the microscopic level, no inflammation was observed in lung tissue of IFNγ -/- mice in response to CCL3 overexpression alone [Figure 5B]. In contrast, significant pathology was observed in lung tissue of IFNγ -/- mice expressing CCL3 and supplemented with exogenous IFNγ. Findings include moderate peribronchiolar granulocytic infiltration and substantial parenchymal involvement but minimal edema fluid within the bronchioles and in the parenchymal tissue [Figure 5C]. Interestingly, weight loss is sustained among the mice overexpressing CCL3 while receiving supplemental IFNγ over the 9 day examination period [Figure 5D], but, despite the substantial inflammatory response, we observe no progression to respiratory failure up to and including t = 14 days.

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: SUNY Upstate Medical University, Syracuse, New York 13210, USA. bonvillc@upstate.edu

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.

Show MeSH
Related in: MedlinePlus