MyD88-dependent induction of allergic Th2 responses to intranasal antigen

Piggott, Damani A.; Eisenbarth, Stephanie C.; Xu, Lan; Constant, Stephanie L.; Huleatt, James W.; Herrick, Christina A.; Bottomly, Kim

doi:10.1172/jci200522462

Cited by 205 publications

(177 citation statements)

References 45 publications

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“…For example, asthma, which is characterized by a Th2-like environment (24), is exacerbated by low-dose LPS compared with high-dose LPS. Similarly, pDCs dampen lung inflammation into the lung of OVA-sensitized mice and in mice treated with cigarette extracts (10,42), proving their suppressive immune activity. In our experimental conditions we observed a similar path, as the ablation of pDCs in tumorbearing mice that were treated with low-dose LPS favored tumor arrest in contrast to mice treated with the high-dose LPS, implying a central role for pDCs in tumor progression in this model.…”

Section: Discussionmentioning

confidence: 92%

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Plasmacytoid Dendritic Cells Play a Key Role in Tumor Progression in Lipopolysaccharide-Stimulated Lung Tumor–Bearing Mice

Rega

Terlizzi

Luciano

et al. 2013

The Journal of Immunology

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The antitumor activity of LPS was first described by Dr. William Coley. However, its role in lung cancer remains unclear. The aim of our study was to elucidate the dose-dependent effects of LPS (0.1–10 μg/mouse) in a mouse model of B16-F10–induced metastatic lung cancer. Lung tumor growth increased at 3 and 7 d after the administration of low-dose LPS (0.1 μg/mouse) compared with control mice. This was associated with an influx of plasmacytoid dendritic cells (pDCs), regulatory T cells, myeloid-derived suppressor cells, and CD8+ regulatory T cells. In contrast, high-dose LPS (10 μg/mouse) reduced lung tumor burden and was associated with a greater influx of pDCs, as well as a stronger Th1 and Th17 polarization. Depletion of pDCs during low-dose LPS administration resulted in a decreased lung tumor burden. Depletion of pDCs during high-dose LPS treatment resulted in an increased tumor burden. The dichotomy in LPS effects was due to the phenotype of pDCs, which were immunosuppressive after the low-dose LPS, and Th1- and T cytotoxic–polarizing cells after the high-dose LPS. Adoptive transfer of T cells into nude mice demonstrated that CD8+ T cells were responsible for pDC recruitment following low-dose LPS administration, whereas CD4+ T cells were required for pDC influx after the high-dose LPS. In conclusion, our data suggest differential effects of low-dose versus high-dose LPS on pDC phenotype and tumor progression or regression in the lungs of mice.

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Section: Discussionmentioning

confidence: 92%

“…LPS elicits airway inflammation via the activation of TLR4 in a MyD88-dependent manner (10). However, the dose of LPS is of essential importance because low levels of LPS can induce a Th2-like immunity, whereas high levels of LPS induce Th1 responses in a mouse model of airway sensitization (11).…”

mentioning

confidence: 99%

Plasmacytoid Dendritic Cells Play a Key Role in Tumor Progression in Lipopolysaccharide-Stimulated Lung Tumor–Bearing Mice

Rega

Terlizzi

Luciano

et al. 2013

The Journal of Immunology

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“…An extensive literature examines the role of the MyD88 adaptor protein in Th1 vs. Th2 activation [26][27][28]. This led to a working consensus that MyD88-dependent signaling is preferentially required for Th1 responses, although it can also play a role in Th2 induction under some circumstances [29]. The MyD88-independent signaling pathways preferentially eliciting development of Th2-biased responses are not well characterized.…”

Section: Discussionmentioning

confidence: 99%

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

et al. 2007

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Phosphoinositide 3-kinases (PI3K) regulate immune activation via their roles in signal transduction of multiple classes of receptors. Here, we examined the effect of genetic inactivation of the hemopoietic cell-restricted PI3K isoform p110d on systemic cytokine and chemokine responses and allergic airway inflammation. We found that type 2 cytokine responses (IL-4, IL-5 and IL-13) are significantly decreased in p110d mutants, whereas type 1 cytokine responses (IFN-c and CXCL10) were robust. Elevated IFN-c production during the primary response to ovalbumin (OVA) was associated with reduced production of the regulatory cytokine IL-10. IFN-c and IL-10 production normalized after secondary OVA immunization; however, type 2 cytokine production was persistently reduced. Type 2 cytokine-dependent airway inflammation elicited by intranasal challenge with OVA was dramatically reduced, with reduced levels of eosinophil recruitment and mucus production observed in the lungs. Induction of respiratory hyper-responsiveness to inhaled methacholine, a hallmark of asthma, was markedly attenuated in p110d-inactivated mice. Adoptive transfer of OVA-primed splenocytes from normal but not p110d-inactivated mice could induce airway eosinophilia in naive, airway-challenged recipient mice. These data demonstrate a novel functional role for p110d signaling in induction of type 2 responses in vivo and may offer a new therapeutic target for Th2-mediated airway disease. IntroductionPhosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating immune function [1,2]. PI3K are activated by stimulation through a variety of receptor types, including antigen receptors, costimulatory receptors and certain cytokine receptors. PI3K function by phosphorylating specific plasma membrane phospholipids to generate short-lived, membrane-integral lipid [3,4]. Effects of regulatory subunit deficiencies on T cells are less clear: deficiency of the p85a regulatory subunit for class 1A PI3K was reported to have no effect on T cell activation in vitro, while deficiency in the p85b regulatory subunit increased T cell proliferation in vitro [5]. One group found that p85-deficient mice have enhanced responses to Leishmania infection [6], but reduced immunity to nematode infection [7], suggesting that impaired class IA PI3K signaling leads to an immune dysregulation rather than a general immunodeficiency. However, the interpretation of these studies is complicated because regulatory subunits each affect the stability and activity of multiple catalytic subunits and may have adaptor functions in signaling independent of PI3K catalytic subunits.Recent work has begun to explore the specific roles of different PI3K catalytic subunit isoforms in immune function. Analysis of p110a and p110b deficiency has been hindered by the lethality of these mutations [8,9]. Mice deficient in the class IB subunit p110c are viable and have defects in T cell development and activation, as well as severe defects in neutrophil function, while B cell activation appears normal [1...

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“…The immune response is a highly regulated event involving a number of sophisticated and cross-regulated pathways shared by cellular players of the innate and acquired immune system (52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62). Whereas the TLRs are known to be underpinnings of the innate immune response, they are also intimately involved in events that direct the adaptive immune response (49)(50)(51).…”

Section: Tlrs and The Adaptor Molecule Myeloid Differentiation Factormentioning

confidence: 99%

“…Interestingly, the lack of IL-12 production via limited TLR activation during the inflammatory/immune response appears to lead to Th2 responses, suggesting that this type of response is a default pathway that occurs in the absence of IL-12. Investigations have demonstrated that MyD88 knockout mice were not able to generate a Th1 response when challenged with an infectious agent (57)(58)(59)(63)(64)(65)(66). Also, MyD88-mediated cytokines appear to provide a suppressive signal for a Th2-type response.…”

Section: Notch Ligands Regulate Cytokine-dependent Responses and Partmentioning

confidence: 99%

Toll-like Receptors, Notch Ligands, and Cytokines Drive the Chronicity of Lung Inflammation

Raymond

Schaller²,

Hogaboam

et al. 2007

Proceedings of the American Thoracic Society

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MyD88-dependent induction of allergic Th2 responses to intranasal antigen

Abstract: MyD88 is a common

Cited by 205 publications

References 45 publications

Plasmacytoid Dendritic Cells Play a Key Role in Tumor Progression in Lipopolysaccharide-Stimulated Lung Tumor–Bearing Mice

Plasmacytoid Dendritic Cells Play a Key Role in Tumor Progression in Lipopolysaccharide-Stimulated Lung Tumor–Bearing Mice

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

Toll-like Receptors, Notch Ligands, and Cytokines Drive the Chronicity of Lung Inflammation

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