C‐C chemokine receptor 2 (CCR2) deficiency improves bleomycin‐induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage‐derived matrix metalloproteinases

Okuma, Toshitada; Terasaki, Yasuhiro; Kaikita, Koichi; Kobayashi, Hironori; Kuziel, William A.; Kawasuji, Michio; Takeya, Motohiro

doi:10.1002/path.1667

Cited by 157 publications

(132 citation statements)

References 47 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…MCP-1 has previously been reported to be a major profibrotic chemokine involved in various fibrotic processes, including recruitment of fibrocytes, induction of collagen synthesis, and up-regulation of TGF-␤1 expression in various models. 50,51,[55][56][57][58][59][60][61][63][64][65][66][67][68] Indeed, we observed that MCP-1 responses preceded the responses of fibrogenic growth factor TGF-␤1, 51,52 which were significantly higher in the lung of infected TNF Ϫ/Ϫ lungs and were well correlated with fibrotic tissue remodeling seen in TNF Ϫ/Ϫ lungs at later time points during influenza infection. Thus, depletion of MCP-1 in influenza-infected TNF Ϫ/Ϫ hosts markedly reduced lung immunopathology and tissue remodeling, and such MCP-1 depletion-improved welfare was associated with diminished production of bioactive TGF-␤1.…”

Section: Discussionmentioning

confidence: 83%

“…51,[62][63][64][65][66][67][68] Thus, given the dysregulated MCP-1 and its association with heightened TGF-␤1 production seen in influenza-infected TNF Ϫ/Ϫ lungs (Figure 7), we further investigated the role of MCP-1 in heightened immunopathology and fibrotic reaction in the lung of TNF Ϫ/Ϫ mice by means of MCP-1 depletion. To this end, MCP-1 anti-serum (anti-MCP-1) or the control serum was administered intraperitoneally to TNF Ϫ/Ϫ mice on days 2, 5, and 9 following influenza infection, and the mice were sacrificed at day 21 after infection for morphometric quantification of lung immunopathology and fibrotic remodeling ( Figure 8A).…”

Section: Attenuation Of Lung Immunopathology In Influenza-infected Tnmentioning

confidence: 99%

See 1 more Smart Citation

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Damjanovic

Divangahi

Kugathasan

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Lung immunopathology is the main cause of influenzamediated morbidity and death, and much of its molecular mechanisms remain unclear. Whereas tumor necrosis factor-␣ (TNF-␣) is traditionally considered a proinflammatory cytokine, its role in influenza immunopathology is unresolved. We have investigated this issue by using a model of acute H1N1 influenza infection established in wild-type and TNF-␣-deficient mice and evaluated lung viral clearance, inflammatory responses, and immunopathology. Whereas TNF-␣ was up-regulated in the lung after influenza infection, it was not required for normal influenza viral clearance. However, TNF-␣ deficiency led not only to a greater extent of illness but also to heightened lung immunopathology and tissue remodeling. The severe lung immunopathology was associated with increased inflammatory cell infiltration, anti-influenza adaptive immune responses, and expression of cytokines such as monocyte chemoattractant protein-1 (MCP-1) and fibrotic growth factor, TGF-␤1. Thus, in vivo neutralization of MCP-1 markedly attenuated lung immunopathology and blunted TGF-␤1 production following influenza infection in these hosts. On the other hand, in vivo transgenic expression of MCP-1 worsened lung immunopathology following influenza infection in wild-type hosts. Thus, TNF-␣ is dispensable for influenza clearance; however, different from the traditional belief, this cytokine is critically required for negatively regulating the extent of lung immunopathology during acute influenza infection.

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Attenuation Of Lung Immunopathology In Influenza-infected Tnmentioning

confidence: 99%

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Damjanovic

Divangahi

Kugathasan

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…MCP-1 may also promote the fibrotic phenotype. For instance, mice lacking CCR2 or overexpressing mutant MCP-1 are protected against bleomycin-induced lung fibrosis (28,29). Intriguingly, elevated levels of MCP-1 have been detected in lavage fluid obtained from children with interstitial lung disease (44).…”

Section: Discussionmentioning

confidence: 98%

“…Although MCP-1 is chemotactic for monocytes and macrophages, studies have led to an appreciation that it also promotes fibrosis in response to bleomycin (28,29) and affects the inflammatory response to influenza A virus infection (26). To determine whether elevated levels of MCP-1 were associated with fibrosis, lung histology was investigated during infection.…”

Section: Neonatal Hyperoxia Promotes Fibrosis In Infected Adult Micementioning

confidence: 99%

Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected with Influenza A Virus

O’Reilly

Marr

Yee

et al. 2008

Am J Respir Crit Care Med

112

124

View full text Add to dashboard Cite

Rationale: Lungs of adult mice exposed to hyperoxia as newborns are simplified and exhibit reduced function much like that observed in people who had bronchopulmonary dysplasia (BPD) as infants. Because survivors of BPD also show increased risk for symptomatic respiratory infections, we investigated how neonatal hyperoxia affected the response of adult mice infected with influenza A virus infection. Objectives: To determine whether neonatal hyperoxia increased the severity of influenza A virus infection in adult mice. Methods: Adult female mice exposed to room air or hyperoxia between Postnatal Days 1 and 4 were infected with a sublethal dose of influenza A virus. Measurements and Main Results: The number of macrophages, neutrophils, and lymphocytes observed in airways of infected mice that had been exposed to hyperoxia as neonates was significantly greater than in infected siblings that had been exposed to room air. Enhanced inflammation correlated with increased levels of monocyte chemotactic protein-1 (CCL2) in lavage fluid, whereas infectionassociated changes in IFN-g, IL-1b, IL-6, tumor necrosis factor-a, KC, granulocyte-macrophage colony-stimulating factor, and macrophage inflammatory protein-1a, and production of virus-specific antibodies, were largely unaffected. Increased mortality of mice exposed to neonatal hyperoxia occurred by Day 14 of infection, and was associated with persistent inflammation and fibrosis. Conclusions: These data suggest that the disruptive effect of hyperoxia on neonatal lung development also reprograms key innate immunoregulatory pathways in the lung, which may contribute to exacerbated pathology and poorer resistance to respiratory viral infections typically seen in people who had BPD.

show abstract

“…However, in a model of bleomycin-induced pulmonary fibrosis, it was suggested that MCP-1 might regulate MMP-9 expression; however, no direct evidence was provided. 33 In addition, reduced expression of MMP-9 in MCP-1-null macrophages can be restored by addition of TNF-␣, an acute-phase proinflammatory cytokine with a role in the foreign body response that has received little attention. 6,34 TNF-␣ also induces apoptosis in macrophages adherent to biomaterials, and IL-4 inhibits the apoptosisinducing abilities of TNF-␣.…”

Section: Discussionmentioning

confidence: 99%

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Skokos

Charokopos

Khan

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Homotypic cell fusion occurs in several cell types including macrophages in the formation of foreign body giant cells. Previously, monocyte chemoattractant protein-1 (MCP-1) was demonstrated to be required for foreign body giant cell formation in the foreign body response. The present study investigated the fusion defect in MCP-1-null macrophages by implanting biomaterials intraperitoneally in wildtype and MCP-1-null mice and monitoring the macrophage response at 12 hours to 4 weeks. MCP-1-null mice exhibited reduced accumulation and fusion of macrophages on implants, which was associated with attenuation of the foreign body response. Consistent with previous in vitro findings, the level of matrix metalloproteinase-9 (MMP-9) was reduced in MCP-1-null macrophages adherent to implants. In contrast, CCR2 expression was unaffected. In vitro studies revealed reduced tumor necrosis factor-␣ (TNF-␣) production and abnormal subcellular redistribution of E-cadherin and ␤-catenin during fusion in MCP-1-null macrophages. Exogenous TNF-␣ caused an increase in the production of MMP-9 and rescued the fusion defect. Addition of GM6001 (MMP inhibitor) or NSC23766 (Rac1 inhibitor) indicated two distinct induction pathways, one for E-cadherin/␤-catenin and one for MCP-1, TNF-␣, and MMP-9. Considered together, these observations demonstrate that induction of E-cadherin/␤-catenin is not sufficient for fusion in the absence of MCP-1 or the downstream mediators TNF-␣ and MMP-9. Moreover, attenuation of the foreign body response in intraperitoneal implants in MCP-1-null mice demonstrates that the process depends on tissue-specific factors.

show abstract

C‐C chemokine receptor 2 (CCR2) deficiency improves bleomycin‐induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage‐derived matrix metalloproteinases

Cited by 157 publications

References 47 publications

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected with Influenza A Virus

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Contact Info

Product

Resources

About