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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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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.
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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.

Mentions: In order to examine the independent and interdependent contributions of CCL3 and IFNγ to the process of neutrophil recruitment in vivo, we generated a method for overexpression of CCL3 in vivo. CCL3 was detected in lung tissue homogenates [Figure 4A], reaching levels similar to those detected in lung tissue of mice in response to PVM infection [12]. Immunoreactive CCL3 was detected in bronchial epithelial cells [Figure 4B]. No CCL3-positive cells were detected in lung tissue from mice challenged with control vector (vctrl) [Figure 4C].


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)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2662797&req=5

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.
Mentions: In order to examine the independent and interdependent contributions of CCL3 and IFNγ to the process of neutrophil recruitment in vivo, we generated a method for overexpression of CCL3 in vivo. CCL3 was detected in lung tissue homogenates [Figure 4A], reaching levels similar to those detected in lung tissue of mice in response to PVM infection [12]. Immunoreactive CCL3 was detected in bronchial epithelial cells [Figure 4B]. No CCL3-positive cells were detected in lung tissue from mice challenged with control vector (vctrl) [Figure 4C].

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