CD11b+ Myeloid Cells Are the Key Mediators of Th2 Cell Homing into the Airway in Allergic Inflammation

Medoff, Benjamin D.; Seung, Edward; Hong, Sandra; Thomas, Seddon Y.; Sandall, Barry P.; Duffield, Jeremy S.; Kuperman, Douglas A.; Erle, David J.; Luster, Andrew D.

doi:10.4049/jimmunol.182.1.623

Cited by 112 publications

(115 citation statements)

References 67 publications

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“…Increased expression of Th2-associated chemokines CCL17 and CCL27 [44] further substantiate these findings. We also detected H37Ra-induced B-cell-associated receptors of the TNF receptor family at d30 p.i.…”

Section: Adaptive Immune Responsesupporting

confidence: 72%

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Beisiegel¹,

Mollenkopf²,

Hahnke³

et al. 2009

Eur J Immunol

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Progression and outcome of tuberculosis is governed by extensive crosstalk between pathogen and host. Analyses of global changes in gene expression during immune response to infection with Mycobacterium tuberculosis (M.tb) can help identify molecular markers of disease state and progression. Global distribution of M.tb strains with different degrees of virulence and drug resistance, especially for the immunocompromised host, make closer analyses of host responses more pressing than ever. Here, we describe global transcriptional responses of inducible nitric oxide synthase-deficient (iNOS -/-) and WT mice infected with two related M.tb strains of markedly different virulence, namely the M.tb laboratory strains H37Rv and H37Ra. Both hosts exhibited highly similar resistance to infection with H37Ra. In contrast, iNOS -/-mice rapidly succumbed to H37Rv, whereas WT mice developed chronic course of disease. By differential analyses, virulence-specific changes in global host gene expression were analyzed to identify molecular markers characteristic for chronic versus acute infection. We identified several markers unique for different stages of disease progression and not previously associated with virulencespecific host responses in tuberculosis.

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Section: Adaptive Immune Responsesupporting

confidence: 72%

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Beisiegel¹,

Mollenkopf²,

Hahnke³

et al. 2009

Eur J Immunol

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“…Recent work implicates pulmonary epithelial cell-produced SDF-1 in later phase neutrophil recruitment (5), but the role of the innate immune cellular response in regulating the ongoing neutrophil influx is not clearly defined. PBMs are increasingly being recognized in many organ systems as orchestrators of leukocyte recruitment (11,22), prime initiators of endothelial damage (44,45), and pivotal contributors to fibrogenesis (32,46). However, despite the significant body of work suggesting that monocytes contribute to ALI (11,13,16,39,44,45,(47)(48)(49), no published reports exist of therapeutic monocyte depletion in established experimental ALI.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, studies have highlighted the role played by the resident alveolar macrophage (AM) in eliciting the inflammatory response in ALI through orchestration of early chemokine responses (20,21). In contrast to models used to study anatomical compartments such as the peritoneum and pleura (18,19), it is possible to selectively ablate the PBM compartment without affecting resident AMs in murine models of lung inflammation (22). We used three independent techniques to deplete PBMs: systemic liposomal clodronate (sLC), diphtheria toxin (DT) administration in CD11b diphtheria toxin receptor (DTR) mice, and targeted antibody-dependent cell-mediated cytotoxic (ADCC) depletion of monocytes (Table 1).…”

mentioning

confidence: 99%

Monocytes Control Second-Phase Neutrophil Emigration in Established Lipopolysaccharide-induced Murine Lung Injury

Dhaliwal

Scholefield

Ferenbach

et al. 2012

Am J Respir Crit Care Med

109

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Rationale: Acute lung injury (ALI) is an important cause of morbidity and mortality, with no currently effective pharmacological therapies. Neutrophils have been specifically implicated in the pathogenesis of ALI, and there has been significant research into the mechanisms of early neutrophil recruitment, but those controlling the later phases of neutrophil emigration that characterize disease are poorly understood. Objectives: To determine the influence of peripheral blood monocytes (PBMs) in established ALI. Methods: In a murine model of LPS-induced ALI, three separate models of conditional monocyte ablation were used: systemic liposomal clodronate (sLC), inducible depletion using CD11b diphtheria toxin receptor (CD11b DTR) transgenic mice, and antibodydependent ablation of CCR2 hi monocytes. Measurements and Main Results: PBMs play a critical role in regulating neutrophil emigration in established murine LPS-induced lung injury. Gr1 hi and Gr1 lo PBM subpopulations contribute to this process. PBM depletion is associated with a significant reduction in measures of lung injury. The specificity of PBM depletion was demonstrated by replenishment studies in which the effects were reversed by systemic PBM infusion but not by systemic or local pulmonary infusion of mature macrophages or lymphocytes. Conclusions: These results suggest that PBMs, or the mechanisms by which they influence pulmonary neutrophil emigration, could represent therapeutic targets in established ALI. Keywords: acute lung injury; LPS; monocytes; neutrophilsThe innate inflammatory response is geared to the clearance of pathogens, but excessive and persistent granulocyte accumulation is detrimental to the host (1). Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are characterized by neutrophil-mediated lung injury, the most common etiology being severe sepsis (2). Neutrophil-mediated lung injury of the epithelial/endothelial interface and consequent vascular leak are the hallmarks of ALI/ARDS (2-4). There are 200,000 cases per year of ALI in the United States, with a mortality of approximately 40% (2). No pharmacological agents have been shown convincingly to affect mortality. There is thus a pressing need to define critical mediators of neutrophil recruitment and to implement specific, mechanismbased therapeutic interventions.The neutrophilic response in ALI has been described as occurring in two distinct phases (5): an initial "recruitment phase" mediated by chemokines followed by a "persistent phase" of neutrophil recruitment, possibly mediated in part by stromal-derived factor-1 (SDF-1/CXCL12) (5). Patients often present with established lung inflammation, and interventions must therefore be guided toward this second phase of neutrophil recruitment to reduce lung injury and ventilator dependence. The underlying cellular mechanisms driving this second phase of neutrophil recruitment remain to be fully characterized.Peripheral blood monocytes (PBMs) are recruited alongside neutrophils in acute inflammati...

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“…These proinflammatory effects of IL-13 are mediated by the IL-13 receptor, which, upon ligation, induces tyrosine phosphorylation of the STAT6 transcription factor (1,4). Once phosphorylated, STAT6 dimerizes and translocates to the nucleus where it binds to DNA and initiates expression of a number of genes, including chemokines such as CCL11 (eotaxin-1) and CCL17 (thymus and activation-regulated chemokine), which then promote eosinophil and leukocyte infiltration into the lung (5)(6)(7)(8).…”

mentioning

confidence: 99%

Dose-Dependent Effects of IL-17 on IL-13–Induced Airway Inflammatory Responses and Airway Hyperresponsiveness

Kinyanjui

Shan

Nakada

et al. 2013

The Journal of Immunology

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The Th2 cytokine IL-13 regulates several aspects of the asthmatic phenotype, including airway inflammation, airway hyperresponsiveness, and mucus production. The Th17 cytokine IL-17A is also implicated in asthma and has been shown to both positively and negatively regulate Th2-dependent responses in murine models of allergic airways disease. Our objective in this study was to better understand the role of IL-17 in airway inflammation by examining how IL-17 modifies IL-13–induced airway inflammatory responses. We treated BALB/c mice intranasally with IL-13 or IL-17 alone or in combination for 8 consecutive days, after which airway hyperresponsiveness, inflammatory cell influx into the lung, and lung chemokine/cytokine expression were assessed. As expected, IL-13 increased airway inflammation and airway hyperresponsiveness. IL-13 also increased numbers of IL-17–producing CD4+ and γδ T cells. Treating mice with a combination of IL-13 and IL-17 reduced infiltration of IL-17+ γδ T cells, but increased the number of infiltrating eosinophils. In contrast, coadministration of IL-13 with a higher dose of IL-17 decreased all IL-13–induced inflammatory responses, including infiltration of both IL-17+CD4+ and γδ T cells. To examine the inhibitory activity of IL-17–expressing γδ T cells in this model, these cells were adoptively transferred into naive recipients. Consistent with an inhibitory role for γδ T cells, IL-13–induced infiltration of eosinophils, lymphocytes, and IL-17+CD4+ T cells was diminished in recipients of the γδ T cells. Collectively, our data indicate that allergic airway inflammatory responses induced by IL-13 are modulated by both the quantity and the cellular source of IL-17.

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CD11b+ Myeloid Cells Are the Key Mediators of Th2 Cell Homing into the Airway in Allergic Inflammation

Cited by 112 publications

References 67 publications

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Monocytes Control Second-Phase Neutrophil Emigration in Established Lipopolysaccharide-induced Murine Lung Injury

Dose-Dependent Effects of IL-17 on IL-13–Induced Airway Inflammatory Responses and Airway Hyperresponsiveness

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