Antifungal and Airway Remodeling Roles for Murine Monocyte Chemoattractant Protein-1/CCL2 During Pulmonary Exposure to<i>Asperigillus fumigatus</i>Conidia

Blease, Kate; Mehrad, Borna; Lukacs, Nicholas W.; Kunkel, Steven L.; Standiford, Theodore J.; Hogaboam, Cory M.

doi:10.4049/jimmunol.166.3.1832

Cited by 65 publications

(59 citation statements)

References 51 publications

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“…Excessive accumulation of these inflammatory cells in the lung contributes to severe immunopathology and tissue injury that precipitates tissue remodeling. 8,19,51,52,56,69 The dysregulated anti-influenza T-cell responses that we observed in infected TNF Ϫ/Ϫ or TNF-depleted hosts are likely due in part to reduced T-cell contraction following viral clearance. These results are consistent with studies of intracellular mycobacterial and LCMV infections.…”

Section: Discussionmentioning

confidence: 90%

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

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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.

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Section: Discussionmentioning

confidence: 90%

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

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“…Conversely, IL-10 has been found to be hepatoprotective in Con A-mediated liver damage, because Ab neutralization of IL-10 exacerbates Con A-mediated hepatic injury (10). Interestingly, several lines of evidence suggest that CCL2/MCP-1 is associated with the development of a polarized Th2 response (31,43). Therefore, in the present study, we hypothesized that the enhanced hepatic injury observed after CCL2/MCP-1 neutralization in Con A-induced hepatitis could be due to the overproduction of the Th1 cytokines TNF-␣, IL-12, and/or IFN-␥, or a decrease of the Th2 cytokine IL-10.…”

Section: Discussionmentioning

confidence: 99%

“…with anti-MCP-1 antiserum (0.5 ml/mouse) 16 h before Con A administration as previously described (31). Control mice received heat-inactivated normal rabbit serum (NRS; Sigma-Aldrich).…”

Section: Ccl2/mcp-1 Neutralizationmentioning

confidence: 99%

“…CCL2/MCP-1 and cytokine (IL-4, IFN-␥, TNF-␣, IL-12, and IL-10) levels were determined in liver tissue homogenates after Con A administration by specific ELISAs (31,32). For this, individual perfused livers were homogenized in cold PBS buffer containing protease mixture inhibitor (SigmaAldrich) immediately after their removal as previously described (33).…”

Section: Chemokine and Cytokine Elisasmentioning

confidence: 99%

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C-C Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Directly Inhibits NKT Cell IL-4 Production and Is Hepatoprotective in T Cell-Mediated Hepatitis in the Mouse

Ajuebor

Hogaboam

et al. 2003

The Journal of Immunology

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T cell-mediated liver diseases are associated with elevated serum levels of C-C chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1). However, the extent to which the actions of CCL2/MCP-1 contribute to the pathogenesis of T cell-mediated hepatitis remains incompletely understood. Con A-induced hepatitis is a liver-specific inflammation mediated by activated T cells and is driven by an up-regulation of the hepatic expression of TNF-α, IFN-γ, and IL-4. The present study examined the role of CCL2/MCP-1 in the pathogenesis of T cell-mediated hepatitis induced by Con A administration in the mouse. We demonstrate a novel hepatoprotective role for CCL2/MCP-1 during Con A-induced hepatitis, because CCL2/MCP-1 neutralization strikingly enhanced hepatic injury, both biochemically and histologically, after Con A administration. Furthermore, CCL2/MCP-1 neutralization was associated with a significant reduction in the hepatic levels of TNF-α and IFN-γ, but with a significant increase in hepatic IL-4 levels. Moreover, IL-4 production and CCR2 expression by Con A-stimulated CD3+NK1.1+ T cells was significantly reduced by rMCP-1 treatment in vitro. In summary, we propose that CCL2/MCP-1 fulfills a novel anti-inflammatory role in T cell-mediated hepatitis by inhibiting CD3+NK1.1+ T cell-derived IL-4 production through direct stimulation of its specific receptor CCR2. These findings may have direct clinical relevance to T cell-mediated hepatitis.

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“…Human IL-8/CXCL8, MCP-1/CCL2, and RANTES/CCL5 protein levels were determined in 50-l samples from cell supernatants using a standard sandwich ELISA technique previously described in detail (5). In brief, Nunc-immuno ELISA plates (Fisher Scientific, Springfield, NJ) were coated with the appropriate polyclonal capture Ab (R&D Systems), washed, and blocked with 2% BSA/PBS.…”

Section: Elisa Analysis Of Chemokine Protein In Cell Supernatantsmentioning

confidence: 99%

Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells

Lukacs

Kunkel

2002

The Journal of Immunology

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The CC chemokine eotaxin/CCL11 is known to bind to the receptor CCR3 on eosinophils and Th2-type lymphocytes. In this study, we demonstrate that CCR3 is expressed on a subpopulation of primary human dermal microvascular endothelial cells and is up-regulated by TNF-α. We found that incubation of human dermal microvascular endothelial cells with recombinant eotaxin/CCL11 suppresses TNF-α-induced production of the neutrophil-specific chemokine IL-8/CXCL8. The eotaxin/CCL11-suppressive effect on endothelial cells was not seen on IL-1β-induced IL-8/CXCL8 release. Eotaxin/CCL11 showed no effect on TNF-α-induced up-regulation of growth-related oncogene-α or IFN-γ-inducible protein-10, two other CXC chemokines tested, and did not affect production of the CC chemokines monocyte chemoattractant protein-1/CCL2 and RANTES/CCL5, or the adhesion molecules ICAM-1 and E-selectin. These results suggest that eotaxin/CXCL11 is not effecting a general suppression of TNF-αR levels or signal transduction. Suppression of IL-8/CXCL8 was abrogated in the presence of anti-CCR3 mAb, pertussis toxin, and wortmannin, indicating it was mediated by the CCR3 receptor, Gi proteins, and phosphatidylinositol 3-kinase signaling. Eotaxin/CCL11 decreased steady state levels of IL-8/CXCL8 mRNA in TNF-α-stimulated cells, an effect mediated in part by an acceleration of IL-8 mRNA decay. Eotaxin/CCL11 may down-regulate production of the neutrophil chemoattractant IL-8/CXCL8 by endothelial cells in vivo, acting as a negative regulator of neutrophil recruitment. This may play an important biological role in the prevention of overzealous inflammatory responses, aiding in the resolution of acute inflammation or transition from neutrophilic to mononuclear/eosinophilic inflammation.

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Antifungal and Airway Remodeling Roles for Murine Monocyte Chemoattractant Protein-1/CCL2 During Pulmonary Exposure toAsperigillus fumigatusConidia

Cited by 65 publications

References 51 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

C-C Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Directly Inhibits NKT Cell IL-4 Production and Is Hepatoprotective in T Cell-Mediated Hepatitis in the Mouse

Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells

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