Dataset Information

Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-?B Activation to Prevent Unwarranted Immune Activation.

ABSTRACT: Inhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic cells and macrophages, take up inhaled antigens, the cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, such as activation of the transcription factor NF-?B, are not well understood. Here, we show that the nuclear receptor PPAR? plays a critical role in blocking NF-?B activation in response to inhaled antigens to preserve immune tolerance. Tolerance induction promoted mitochondrial respiration, generation of H2O2, and suppression of NF-?B activation in WT, but not PPAR?-deficient, APCs. Forced restoration of H2O2 in PPAR?-deficient cells suppressed I?B? degradation and NF-?B activation. Conversely, scavenging reactive oxygen species from mitochondria promoted I?B? degradation with loss of regulatory and promotion of inflammatory T cell responses in vivo. Thus, communication between PPAR? and the mitochondria maintains immune quiescence in the airways.

SUBMITTER: Khare A

PROVIDER: S-EPMC4880515 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-κB Activation to Prevent Unwarranted Immune Activation.

Khare Anupriya A Raundhal Mahesh M Chakraborty Krishnendu K Das Sudipta S Corey Catherine C Kamga Christelle K CK Quesnelle Kelly K St Croix Claudette C Watkins Simon C SC Morse Christina C Oriss Timothy B TB Huff Rachael R Hannum Rachel R Ray Prabir P Shiva Sruti S Ray Anuradha A

Cell reports 20160512 8

Inhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic cells and macrophages, take up inhaled antigens, the cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, such as activation of the transcription factor NF-κB, are not well understood. Here, we show that the nuclear receptor PPARγ plays a critical role in blocking NF-κB activation ...[more]

PMID: 27184852

Similar Datasets

Project description:BackgroundInhalational antigen tolerance typically protects against the development of allergic airway disease but may be overcome to induce allergic sensitization preceding the development of asthma.ObjectivesWe examined in vivo whether pre-existing inhalational antigen tolerance could be overcome by activation of the transcription factor NF-κB in conducting airway epithelial cells, and used a combination of in vivo and in vitro approaches to examine the mechanisms involved.MethodsWild-type and transgenic mice capable of expressing constitutively active IκB kinase β (CAIKKβ) in airway epithelium were tolerized to inhaled ovalbumin. Twenty-eight days later, the transgene was transiently expressed and mice were exposed to inhaled OVA on Day 30 in an attempt to overcome inhalational tolerance.ResultsFollowing ovalbumin challenge on days 40-42, CAIKKβ mice in which the transgene had been activated exhibited characteristic features of allergic airway disease, including airway eosinophilia and methacholine hyper-responsiveness. Increases in the CD103(+) and CD11b(HI) lung dendritic cell populations were present in CAIKKβ mice on Day 31. Bronchoalveolar lavage from mice expressing CAIKKβ mice induced CD4(+) T cells to secrete T(H)2 and T(H)17 cytokines, an effect that required IL-4 and IL-1 signalling, respectively. CAIKKβ mice on Dox demonstrated increased numbers of innate lymphoid type 2 cells (ILC2) in the lung, which also exhibited elevated mRNA expression of the T(H)2-polarizing cytokine IL-4. Finally, airway epithelial NF-kB activation induced allergic sensitization in CAIKKβ mice on Dox that required IL-4 and IL-1 signalling in vivo.ConclusionsOur studies demonstrate that soluble mediators generated in response to airway epithelial NF-κB activation orchestrate the breaking of inhalational tolerance and allergic antigen sensitization through the effects of soluble mediators, including IL-1 and IL-4, on pulmonary dendritic cells as well as innate lymphoid and CD4(+) T cells.

Project description:Inflammation-induced bone erosion is a major pathological factor in several chronic inflammatory diseases that often cause severe outcomes, such as rheumatoid arthritis and periodontitis. Plenty of evidences indicated that the inflammatory bone destruction was attributed to an increase in the number of bone-resorbing osteoclasts. However, anti-resorptive therapy alone failed to prevent bone loss in an inflammatory condition. Conventional anti-inflammation treatments are usually intended to suppress inflammation only, but ignore debilitating the subsequent bone destruction. Therefore, inhibition of proinflammatory activation of osteoclastogenesis could be an important strategy for the development of drugs aimed at preventing inflammatory bone destruction. Methods: In this study, we synthesized a peptide coated gold cluster to evaluate its effects on inflammatory osteoclastogenesis in vitro and inflammation-induced bone destruction in vivo. The in vitro anti-inflammation and anti-osteoclastogenesis effects of the cluster were evaluated in LPS-stimulated and receptor activator of nuclear factor κB ligand (RANKL) stimulated macrophages, respectively. The LPS-induced expression of crucial pro-inflammation cytokines and RANKL-induced osteoclastogenesis as well as the activation of NF-κB pathway in both situations were detected. The inflammation-induced RANKL expression and subsequent inflammatory bone destruction in vivo were determined in collagen-immunized mice. Results: The gold cluster strongly suppresses RANKL-induced osteoclast formation via inhibiting the activation of NF-κB pathway in vitro. Moreover, treatment with the clusters at a dose of 5 mg Au/kg.bw significantly reduces the severity of inflammation-induced bone and cartilage destruction in vivo without any significant toxicity effects. Conclusion: Therefore, the gold clusters may offer a novel potent therapeutic stratagem for inhibiting chronic inflammation associated bone destruction.

Dataset Information

Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-?B Activation to Prevent Unwarranted Immune Activation.

Publications

Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-κB Activation to Prevent Unwarranted Immune Activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets