Enhanced Pulmonary Allergic Responses to<i>Aspergillus</i>in CCR2−/− Mice

Blease, Kate; Mehrad, Borna; Standiford, Theodore J.; Lukacs, Nicholas W.; Gosling, J. A.; Boring, Landin; Charo, Israel F.; Kunkel, Steven L.; Hogaboam, Cory M.

doi:10.4049/jimmunol.165.5.2603

Cited by 146 publications

(108 citation statements)

References 41 publications

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“…For example, in the bleomycin pulmonary injury model, CCR2 deletion is associated with less late collagen accumulation (9,11). In contrast, and more similar to the present findings, deletion of CCR2 was associated with significantly greater organ fibrosis in a pulmonary model of infection and a model of mechanical vascular injury (48,49). Thus, the local environment and mechanism of injury may be the driving factor of how CCR2 signaling contributes to the fibrotic response.…”

Section: Discussioncontrasting

confidence: 55%

Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model

Henke

Pearce

Moaveni

et al. 2006

The Journal of Immunology

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106

177

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CCR2 is required for monocyte recruitment in many inflammatory processes, as well as conferring Th1 lymphokine responses. Deep vein thrombosis (DVT) resolution represents a specific inflammatory response whereby the thrombus must be dissolved for restoration of blood flow. Using a stasis model of DVT in the mouse, we investigated the role of CCR2 on DVT resolution. Genetic deletion of CCR2 (CCR2−/−) was associated with larger thrombi at early and later time points, increased thrombus collagen, fewer thrombus monocytes (F4/80), and significantly impaired neovascularization. IL-2 and IFN-γ were significantly reduced in early CCR2−/− thrombi, whereas MCP-1 was significantly increased, and Th2 lymphokines were unaffected. Supplementation of CCR2−/− mice with IFN-γ normalized early thrombus resolution without increasing monocyte influx. Neither Ab depletion of IFN-γ nor genetic deletion of IFN-γ impaired early DVT resolution. Early fibrinolysis was not impaired in CCR2−/− mice, but a significant reduction in both matrix metalloproteinase (MMP)-2 and MMP-9 activity was observed. However, only MMP-9 activity was restored with administration of IFN-γ. We conclude that an early CCR2-dependent Th1 lymphokine response predominates in normal DVT resolution, mediates this in part by MMP-9 activation, but is not solely dependent on IFN-γ.

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Section: Discussioncontrasting

confidence: 55%

Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model

Henke

Pearce

Moaveni

et al. 2006

The Journal of Immunology

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106

177

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“…Support for this hypothesis and for the contention that IL-13 plays an important role in the pathogenesis of COPD comes from studies that described the emphysema-like decrease in lung elastic recoil in asthma (12) and from our studies that demonstrated that the inducible overexpression of IL-13 in the adult murine lung generated COPD-like inflammation, alveolar enlargement, lung enlargement, enhanced compliance, and mucus metaplasia (13). IL-13 also plays an important role in the pathogenesis of a variety of other disorders including respiratory syncytial virus infection (14), hepatic fibrosis (15), and fungal pneumonitis (16). Surprisingly, the mechanisms that are responsible for IL-13-induced inflammatory, proteolytic, and fibrotic tissue responses are poorly understood.…”

Section: Il-13-induced Chemokine Responses In the Lung: Role Of Ccr2 mentioning

confidence: 97%

“…Although in vitro characterizations would suggest that there is impressive redundancy in this system, examinations of a limited number of ligands in vivo have demonstrated that their production is organized in a coordinated manner and that their effector functions can be restricted to different stages of disease development and/or pathology (17,18,39,44). Thus, in vivo, a deficiency of an individual ligand or its receptor can cause striking alterations in tissue phenotype (16,19). An impressive finding in our study is the potent and rapid induction of MCP-1 and other MCP moieties by IL-13 in the murine lung.…”

Section: Figurementioning

confidence: 99%

“…An impressive finding in our study is the potent and rapid induction of MCP-1 and other MCP moieties by IL-13 in the murine lung. Because MCP-1 signals predominantly via CCR2 and MCP-2, -3, and -5 are also key CCR2 ligands (16,19), the roles of MCP signaling and CCR2 were evaluated by characterizing the IL-13 responses in mice with ϩ/ϩ and Ϫ/Ϫ CCR2 loci. Because prior studies demonstrated that MCP-1 has different effects when exogenously administered during the sensitization vs the elicitation/effector phases of type I and type II granulomatous immune responses (45), care was taken to use a system that allowed the effector mechanisms of IL-13 to be selectively analyzed (see below).…”

Section: Figurementioning

confidence: 99%

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IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

Zhu¹,

Ma²,

Zheng³

et al. 2002

The Journal of Immunology

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179

159

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IL-13 stimulates inflammatory and remodeling responses and contributes to the pathogenesis of human airways disorders. To further understand the cellular and molecular events that mediate these responses, we characterized the effects of IL-13 on monocyte chemotactic proteins (MCPs) and compared the tissue effects of transgenic IL-13 in mice with wild-type (+/+) and null (−/−) CCR2 loci. Transgenic IL-13 was a potent stimulator of MCP-1, -2, -3, and -5. This stimulation was not specific for MCPs because macrophage-inflammatory protein (MIP)-1α, MIP-1β, MIP-2, MIP-3α, thymus- and activation-regulated chemokine, thymus-expressed chemokine, eotaxin, eotaxin 2, macrophage-derived chemokines, and C10 were also induced. The ability of IL-13 to increase lung size, alveolar size, and lung compliance, to stimulate pulmonary inflammation, hyaluronic acid accumulation, and tissue fibrosis, and to cause respiratory failure and death were markedly decreased, whereas mucus metaplasia was not altered in CCR2−/− mice. CCR2 deficiency did not decrease the basal or IL-13-stimulated expression of target matrix metalloproteinases or cathepsins but did increase the levels of mRNA encoding α1-antitrypsin, tissue inhibitor of metalloproteinase-1, -2, and -4, and secretory leukocyte proteinase inhibitor. In addition, the levels of bioactive and total TGF-β1 were decreased in lavage fluids from IL-13 transgenic mice with −/− CCR2 loci. These studies demonstrate that IL-13 is a potent stimulator of MCPs and other CC chemokines and document the importance of MCP-CCR2 signaling in the pathogenesis of the IL-13-induced pulmonary phenotype.

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“…A number of chemokine receptors have also been shown to be important in the development of the airway responses, including CCR1, CCR2, and CCR8. [53][54][55] Relevant data for blocking other receptors, such as CCR3 and CCR4, are still lacking. However, it is likely that multiple receptors contribute to the recruitment of the various cell populations that migrate into the airways after allergen challenge.…”

Section: Discussionmentioning

confidence: 99%

AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity

Lukacs

Berlin

Schols

et al. 2002

The American Journal of Pathology

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195

149

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The role of specific chemokine receptors during allergic asthmatic responses has been relatively undefined. A number of receptors are preferentially expressed on Th2 cells, including CCR4, CCR8, and CxCR4. In the present study, we have examined the role of CxCR4 in the development of cockroach allergen-induced inflammation and airway hyperreactivity in a mouse model of asthma. Using a specific inhibitor of CxCR4, AMD3100, our results indicate that blocking this receptor has a significant effect in down-regulating the inflammation and pathophysiology of the allergen-induced response. Treatment of allergic mice with AMD3100 significantly reduced airway hyperreactivity, peribronchial eosinophilia, and the overall inflammatory responses. In addition, there was a shift in the cytokine profile that was observed in the AMD3100-treated animals. Specifically, there was a significant reduction in interleukin-4 and interleukin-5 levels and a significant increase in interleukin-12 and interferon-␥ levels within the lungs of treated allergic mice. Furthermore, there was a significant alteration in the local chemokine production of CCL22 (MDC) and CCL17 (TARC), two chemokines previously shown to be important in Th2-type allergen responses. Overall, specifically blocking CxCR4 using AMD3100 reduced a number of pathological parameters related to asthmatic-type inflammation.

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Enhanced Pulmonary Allergic Responses toAspergillusin CCR2−/− Mice

Cited by 146 publications

References 41 publications

Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model

Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model

IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity

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