Complement-mediated Regulation Of The IL-17A Axis Is A Central Genetic Determinant Of The Severity Of Experimental Allergic Asthma

Lajoie, Stéphane; Lewkowich, Ian P.; Clark, Jennifer; Sproles, Alyssa; Dienger, Krista; Budelsky, Alison; Wills‐Karp, Marsha

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a5759

Cited by 93 publications

(154 citation statements)

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“…Multiple treatments with a C3a receptor antagonist or anti-C3a mAb inhibit the increase in IL-17 + CD4 + cells in IgE-sensitized mice It has been reported that the inhibition of C3a signaling suppressed the increase in IL-17 + CD4 + cells in the lungs in a murine model of asthma (23). Therefore, we examined whether multiple treatments with the C3a receptor antagonist or anti-C3a mAb during the first three challenges reduced the increased percentage and number of IL-17 + CD4 + cells in the lung at the fourth challenge in our IgEsensitized model.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, it can be speculated that proinflammatory factors produced by the activation of CD4 + cells after the fourth challenge induced the late-phase asthmatic response. Lajoie et al (23) have reported that inhibition of C3a-mediated signaling resulted in fewer lung IL-17 + CD4 + cells in a murine model of allergic asthma. Consistent with this finding, we showed that multiple treatments with a C3a receptor antagonist or antiC3a mAb during the first three Ag challenges suppressed the increases of IL-17 + CD4 + cells in the lungs at the fourth challenge (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that IL-23 is crucial for the maintenance of Th17 cells (34)(35)(36) and the full acquisition of an effector function of Th17 cells (36). The major source of IL-23 is several types of APCs such as activated dendritic cells, monocytes, and macrophages after exposure to pathogen-derived molecules (37)(38)(39)(40); moreover, C3a receptor signaling promotes IL-23 production by dendritic cells (23). Thus, a C3a-mediated IL-23-Th17 axis, which leads to IL-17 production, may be critical for the development of the late-phase asthmatic response and AHR in this IgEsensitized model.…”

Section: Discussionmentioning

confidence: 99%

“…In mouse models of allergic asthma, systemic blockage of IL-17 inhibited the allergen-induced accumulation of neutrophils in the airway and AHR (20)(21)(22), suggesting that IL-17 plays an important role during the pathophysiological process of allergic asthma. Furthermore, Lajoie et al (23) have reported that not only severe AHR but also the increases in IL-17 production and IL-17 + CD4 + cells in asthmatic lungs were reduced in complement C3a receptor-deficient mice. However, the role of IL-17 in allergic asthma has not been fully elucidated, especially in the late-phase asthmatic response; furthermore, the relationship between IL-17 and IgE-mediated asthmatic responses has been unknown.…”

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confidence: 99%

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Complement C3a-Induced IL-17 Plays a Critical Role in an IgE-Mediated Late-Phase Asthmatic Response and Airway Hyperresponsiveness via Neutrophilic Inflammation in Mice

Mizutani

Goshima

Nabe

et al. 2012

The Journal of Immunology

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Allergen-specific IgE plays an essential role in the pathogenesis of allergic asthma. Although there has been increasing evidence suggesting the involvement of IL-17 in the disease, the relationship between IL-17 and IgE-mediated asthmatic responses has not yet been defined. In this study, we attempted to elucidate the contribution of IL-17 to an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness (AHR). BALB/c mice passively sensitized with an OVA-specific IgE mAb were challenged with OVA intratracheally four times. The fourth challenge caused a late-phase increase in airway resistance associated with elevated levels of IL-17+CD4+ cells in the lungs. Multiple treatments with a C3a receptor antagonist or anti-C3a mAb during the challenges inhibited the increase in IL-17+CD4+ cells. Meanwhile, a single treatment with the antagonist or the mAb at the fourth challenge suppressed the late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid. Because IL-17 production in the lungs was significantly repressed by both treatments, the effect of an anti–IL-17 mAb was examined. The late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid was inhibited. Furthermore, an anti–Gr-1 mAb had a similar effect. Collectively, we found that IgE mediated the increase of IL-17+CD4+ cells in the lungs caused by repeated Ag challenges via C3a. The mechanisms leading to the IgE-mediated late-phase asthmatic response and AHR are closely associated with neutrophilic inflammation through the production of IL-17 induced by C3a.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Complement C3a-Induced IL-17 Plays a Critical Role in an IgE-Mediated Late-Phase Asthmatic Response and Airway Hyperresponsiveness via Neutrophilic Inflammation in Mice

Mizutani

Goshima

Nabe

et al. 2012

The Journal of Immunology

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“…In contrast, mice transferred with conventional Th2 or Th17 cells exhibited fewer airway infiltrations of eosinophils or neutrophils, respectively, and limited pathophysiological features (85). Recently, Lajoie et al (86), by using a well-characterized mouse model of differences in susceptibility to severe asthma, showed that the strain of mice that develops severe AHR (A/J mice) produced both IL-17A and Th2 cytokines, whereas the strain that manifests less-severe AHR (C3H/HeJ mice) produced only Th2 cytokines and little to no IL-17A. Blockade of IL-17A in susceptible (A/J) mice decreased the severity AHR, whereas reconstitution of IL-17A in C3H/HeJ mice exacerbated AHR.…”

Section: T Lymphocytes and Asthma Phenotypesmentioning

confidence: 99%

Th17 cells: new players in asthma pathogenesis

Cosmi

Liotta

Maggi

et al. 2011

Allergy

286

198

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CD4+ T effector lymphocytes are distinguished in different subsets on the basis of their patterns of cytokine secretion. Th1 cells, thank to IFN-c production, are responsible for cell-mediated immunity against intracellular pathogens, Th2 cells, through the production of IL-4, provide some degree of protection against helminthes, and Th17 cells, via IL-17, promote neutrophils recruitment for the clearance of bacteria and fungi. However, beyond their protective role, these T-helper subsets can also be involved in the pathogenesis of several inflammatory diseases. Asthma is an inflammatory disease characterized by different clinical phenotypes. Allergic asthma is the result of an inflammatory process driven by allergen-specific Th2 lymphocytes, whereas Th17 cells are mainly involved in those forms of asthma, where neutrophils more than eosinophils, contribute to the inflammation. The identification in allergic asthma of Th17/Th2 cells, able to produce both IL-4 and IL-17, is in keeping with the observation that different clinical phenotypes can coexist in the same patient. In conclusion, a picture in which different T-cell subpopulations are active in different phase of bronchial asthma is emerging, and the wide spectrum of clinical phenotypes is probably the expression of different cellular characters playing a role in lung inflammation.

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The interaction between C5a and both C5aR and C5L2 receptors is required for production of G‐CSF during acute inflammation

et al. 2013

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The complement activation product, C5a, is a key factor for regulation of inflammatory responses. C5a and C5adesArg bind to their receptors, C5aR and C5L2, but the functional roles of C5L2 remain controversial. We screened the patterns of 23 inflammatory mediators in cultures of LPS-activated mouse peritoneal elicited macrophages (PEMs) in the presence or absence of recombinant mouse C5a. Production of most mediators studied was suppressed by C5a, whereas G-CSF production was enhanced. G-CSF gene expression and secretion from PEMs was amplified 2–3-fold by C5a in a dose and time dependent fashion. The degradation product C5adesArg promoted lower levels of G-CSF. The effects of C5a on G-CSF were associated with activation of PI3K/Akt and MEK1/2 signaling pathways. C5a did not enhance G-CSF production in cultures of PEMs from either C5aR-deficient or C5L2-deficient mice, indicating that both C5a receptors are indispensable for mediating the effects of C5a in production of G-CSF. Finally, G-CSF levels in plasma during polymicrobial sepsis after cecal ligation and puncture (CLP) were substantially lower in C5aR-deficient or C5L2-deficient mice as compared to C57BL/6J wild type mice. These findings elucidate the functional characteristics of the C5L2 receptor during the acute inflammatory response.

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Complement-mediated Regulation Of The IL-17A Axis Is A Central Genetic Determinant Of The Severity Of Experimental Allergic Asthma

Cited by 93 publications

References 0 publications

Complement C3a-Induced IL-17 Plays a Critical Role in an IgE-Mediated Late-Phase Asthmatic Response and Airway Hyperresponsiveness via Neutrophilic Inflammation in Mice

Complement C3a-Induced IL-17 Plays a Critical Role in an IgE-Mediated Late-Phase Asthmatic Response and Airway Hyperresponsiveness via Neutrophilic Inflammation in Mice

Th17 cells: new players in asthma pathogenesis

The interaction between C5a and both C5aR and C5L2 receptors is required for production of G‐CSF during acute inflammation

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