Allergic airway disease is unaffected by the absence of IL-4Rα–dependent alternatively activated macrophages

Nieuwenhuizen, Natalie E.; Kirstein, Frank; Jayakumar, Jaisubash; Emedi, Babele; Hurdayal, Ramona; Horsnell, William; Lopata, Andreas L.; Brombacher, Frank

doi:10.1016/j.jaci.2012.03.011

Cited by 53 publications

(59 citation statements)

References 52 publications

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“…We believe this finding is important because numerous studies have employed the LysM Cre mouse to dissect gene function in macrophages. In some diseases, including gastrointestinal nematode infection and allergic airway disease [7], [34], [35] the reported results could be due to a failure to delete the gene of interest in a sufficient proportion of more immature macrophages arising from proliferation or recruitment from monocyte precursors. We found that while mature “resident” tissue macrophages successfully delete the gene of interest, newly differentiating macrophages in inflammatory environments transcribe insufficient Lyz2 to efficiently accomplish the Cre-mediated deletion.…”

Section: Discussionmentioning

confidence: 99%

Incomplete Deletion of IL-4Rα by LysMCre Reveals Distinct Subsets of M2 Macrophages Controlling Inflammation and Fibrosis in Chronic Schistosomiasis

et al. 2014

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Mice expressing a Cre recombinase from the lysozyme M-encoding locus (Lyz2) have been widely used to dissect gene function in macrophages and neutrophils. Here, we show that while naïve resident tissue macrophages from IL-4Rαflox/deltaLysMCre mice almost completely lose IL-4Rα function, a large fraction of macrophages elicited by sterile inflammatory stimuli, Schistosoma mansoni eggs, or S. mansoni infection, fail to excise Il4rα. These F4/80hiCD11bhi macrophages, in contrast to resident tissue macrophages, express lower levels of Lyz2 explaining why this population resists LysMCre-mediated deletion. We show that in response to IL-4 and IL-13, Lyz2loIL-4Rα+ macrophages differentiate into an arginase 1-expressing alternatively-activated macrophage (AAM) population, which slows the development of lethal fibrosis in schistosomiasis. In contrast, we identified Lyz2hiIL-4Rα+ macrophages as the key subset of AAMs mediating the downmodulation of granulomatous inflammation in chronic schistosomiasis. Our observations reveal a limitation on using a LysMCre mouse model to study gene function in inflammatory settings, but we utilize this limitation as a means to demonstrate that distinct populations of alternatively activated macrophages control inflammation and fibrosis in chronic schistosomiasis.

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Section: Discussionmentioning

confidence: 99%

Incomplete Deletion of IL-4Rα by LysMCre Reveals Distinct Subsets of M2 Macrophages Controlling Inflammation and Fibrosis in Chronic Schistosomiasis

et al. 2014

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“…Correlations between asthma severity and numbers of M2-dominant macrophages or their products in lungs and serum of asthmatic patients (3,12) and in mouse models (4) indicate that these cells may actively contribute to disease. On the other hand, it has been shown in mice with abrogated IL-4 receptor-␣ signaling on macrophages that the M2-dominant phenotype is not necessary for allergic lung inflammation and may be a consequence of an elevated Th2 response (16). The finding that anti-inflammatory macrophages were found in lower numbers in HDM-and FDE-exposed mice compared with control mice indicates that this phenotype is prevalent in homeostasis and suggests, that during inflammation, polarization into other macrophage subsets occurs.…”

Section: Discussionmentioning

confidence: 99%

Distinct macrophage phenotypes in allergic and nonallergic lung inflammation

Robbe

Draijer

Borg

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chronic exposure to farm environments is a risk factor for nonallergic lung disease. In contrast to allergic asthma, in which type 2 helper T cell (Th2) activation is dominant, exposure to farm dust extracts (FDE) induces Th1/Th17 lung inflammation, associated with neutrophil infiltration. Macrophage influx is a common feature of both types of lung inflammation, allergic and nonallergic. However, macrophage functions and phenotypes may vary according to their polarized state, which is dependent on the cytokine environment. In this study, we aimed to characterize and quantify the lung macrophage populations in two established murine models of allergic and nonallergic lung inflammation by means of fluorescence-activated cell sorting and immunohistochemistry. We demonstrated that, whereas in allergic asthma M2-dominant macrophages predominated in the lungs, in nonallergic inflammation M1-dominant macrophages were more prevalent. This was confirmed in vitro using a macrophage cell line, where FDE exerted a direct effect on macrophages, inducing M1-dominant polarization. The polarization of macrophages diverged depending on the exposure and inflammatory status of the tissue. Interfering with this polarization could be a target for treatment of different types of lung inflammation.

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“…More recent studies reveal increased M2 macrophages in the lung tissues and BAL fluids of asthma patients and in mouse models of allergic airway infiltration [50–52] and M2 macrophages have been associated with increased asthma/allergic airway inflammation severity [53]. Despite these reports, the role of M2 macrophages in allergic asthma is somewhat controversial and the M2 phenotype has been proposed to be a result of an increased Th2 response [54]. Consistent with our observation that Dex did not reduce HDM-induced Nos2 mRNA expression (M1 marker) in obese mice, Goleva and co-workers showed that steroid resistant asthmatics have more M1 than M2 macrophages in their BAL fluids [55].…”

Section: Discussionmentioning

confidence: 99%

Obesity shifts house dust mite-induced airway cellular infiltration from eosinophils to macrophages: effects of glucocorticoid treatment

et al. 2015

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Although classically characterized by chronic airway inflammation with eosinophil infiltration, asthma is a complex and multifactorial condition with numerous clinical phenotypes. Epidemiological studies strongly support the link between obesity and asthma and suggest that obesity precedes and promotes asthma development, increases asthma severity, and reduces steroid responsivity. Using a house dust mite (HDM) model of airway hyperresponsiveness in C57BL/6 mice, we examined the effects of diet-induced obesity on allergic airway inflammation and its treatment with dexamethasone. When compared to lean mice treated with HDM, obese-HDM mice had reduced plasma adiponectin, an anti-inflammatory adipokine, lower eosinophil and higher macrophage infiltration into the lungs and bronchoalveolar lavage (BAL) fluid, increased expression of total, M1 and M2 macrophage markers in the lungs, and enhanced Th2 and non-Th2 cytokine expression in the lungs. While Th2-associated responses in obese-HDM mice were suppressed by systemic dexamethasone, several Th2-independent responses, including total and M1 macrophage markers in the lungs, and lung CXC-motif ligand 1 (CXCL1) levels, were not improved following dexamethasone treatment. Thus, HDM combined with obesity promotes mixed localized inflammatory responses (e.g. M1, M2, Th1, and Th2) and shifts the cellular infiltration from eosinophils to macrophages, which are less sensitive to dexamethasone regulation. Because obese asthmatics exhibit more severe symptoms, lack a predominance of Th2 biomarkers and are predicted to experience more steroid resistance when compared to lean asthmatics, this model could be used to study blunted steroid responses in obese-HDM mice and to define the macrophages found in the lungs.

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Allergic airway disease is unaffected by the absence of IL-4Rα–dependent alternatively activated macrophages

Cited by 53 publications

References 52 publications

Incomplete Deletion of IL-4Rα by LysMCre Reveals Distinct Subsets of M2 Macrophages Controlling Inflammation and Fibrosis in Chronic Schistosomiasis

Incomplete Deletion of IL-4Rα by LysMCre Reveals Distinct Subsets of M2 Macrophages Controlling Inflammation and Fibrosis in Chronic Schistosomiasis

Distinct macrophage phenotypes in allergic and nonallergic lung inflammation

Obesity shifts house dust mite-induced airway cellular infiltration from eosinophils to macrophages: effects of glucocorticoid treatment

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