Alveolar epithelial cells orchestrate DC function in murine viral pneumonia

Unkel, Barbara; Hoegner, Katrin; Clausen, Björn E.; Landgraf, Peter; Bodner, Johannes; Gattenloehner, Stefan; Janßen, Hermann; Seeger, Werner; Lohmeyer, Juergen; Herold, Susanne

doi:10.1172/jci62139

Cited by 97 publications

(119 citation statements)

References 58 publications

(75 reference statements)

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“…By demonstrating a role for GM-CSF in licensing CD11b + DCs, specific blockade of the CSF-2R signaling pathway on CD11b + DCs might offer a novel therapeutic target. However, CSF-2R signaling on CD103 + DCs has recently been shown to require GM-CSF for optimal influenza virus clearance (60). To summarize, our study demonstrates a critical role of CD11b + DCs in the initiation of Th2 responses to inhaled B. tropicalis allergens and that lung-derived GM-CSF is a key mediator that potentiates their ability to prime and polarize Th2 CD4 + T cells.…”

Section: Discussionmentioning

confidence: 63%

GM-CSF–Licensed CD11b+ Lung Dendritic Cells Orchestrate Th2 Immunity to Blomia tropicalis

Zhou

Schlitzer

et al. 2014

The Journal of Immunology

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The Blomia tropicalis dust mite is prevalent in tropical and subtropical regions of the world. Although it is a leading cause of asthma, little is known how it induces allergy. Using a novel murine asthma model induced by intranasal exposure to B. tropicalis, we observed that a single intranasal sensitization to B. tropicalis extract induces strong Th2 priming in the lung draining lymph node. Resident CD11b+ dendritic cells (DCs) preferentially transport Ag from the lung to the draining lymph node and are crucial for the initiation of Th2 CD4+ T cell responses. As a consequence, mice selectively deficient in CD11b+ DCs exhibited attenuated Th2 responses and more importantly did not develop any allergic inflammation. Conversely, mice deficient in CD103+ DCs and CCR2-dependent monocyte-derived DCs exhibited similar allergic inflammation compared with their wild-type counterparts. We also show that CD11b+ DCs constitutively express higher levels of GM-CSF receptor compared with CD103+ DCs and are thus selectively licensed by lung epithelial-derived GM-CSF to induce Th2 immunity. Taken together, our study identifies GM-CSF–licensed CD11b+ lung DCs as a key component for induction of Th2 responses and represents a potential target for therapeutic intervention in allergy.

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Section: Discussionmentioning

confidence: 63%

GM-CSF–Licensed CD11b+ Lung Dendritic Cells Orchestrate Th2 Immunity to Blomia tropicalis

Zhou

Schlitzer

et al. 2014

The Journal of Immunology

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“…In the presence of inflammatory cytokines released from the lung epithelium and inflammatory cells, e.g. those produced by inflammasome (IL-1β and IL-18) or granulocyte-macrophage colony-stimulating factor (GM-CSF) [110][111][112][113], they are induced to migrate to the draining lymph nodes. In the lymph nodes, CD103 + DCs serve as potent antigen-presenting cells for the activation of naïve CD8 + and CD4 + T-cells and for the presentation of viral antigens to rare virus-specific memory T-cells required for adaptive immunity [114,115].…”

Section: Molecular and Cellular Interactions At The Virus-host Interfacementioning

confidence: 99%

“…Tissue resident alveolar macrophages promote the regeneration of type II alveolar epithelial cells after endotoxin-induced lung injury via a pathway that requires TNF-α and GM-CSF, another proliferative and anti-apoptotic factor for the lung epithelium [156,157]. There is evidence this same pathway is active during the resolution of IAV infection [113].…”

Section: Resolution Of Lung Injury and Alveolar Regenerationmentioning

confidence: 99%

“…In a related approach, small molecule inhibitors of the cellular Raf/ MEK/ERK cascade, which is known to efficiently support viral replication and mediate pro-inflammatory events, confer strong antiviral effects in IAV-infected mice, and are being evaluated in phase I to phase III clinical trials for other indications [186,188]. Finally, GM-CSF, an important mediator of the antiviral host defence and a factor promoting repair of the alveolar epithelium [113,156], has been administered via inhalation to patients with moderate-to-severe pneumonia-associated ARDS (including patients with IAV infection), yielding results supportive of a future clinical trial [189].…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

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Influenza virus-induced lung injury: pathogenesis and implications for treatment

et al. 2015

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The influenza viruses are some of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. Influenza-mediated damage of the airway, alveolar epithelium and alveolar endothelium results from a combination of: 1) intrinsic viral pathogenicity, attributable to its tropism for host airway and alveolar epithelial cells; and 2) a robust host innate immune response, which, while contributing to viral clearance, can worsen the severity of lung injury. In this review, we summarise the molecular events at the virus-host interface during influenza virus infection, highlighting some of the important cellular responses. We discuss immune-mediated viral clearance, the mechanisms promoting or perpetuating lung injury, lung regeneration after influenza-induced injury, and recent advances in influenza prevention and therapy. @ERSpublications We discuss novel aspects of virus-and immune-mediated lung injury and repair after influenza infection

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“…GM‐CSF is important for survival of DCs in non‐lymphoid tissue,25 and the action of GM‐CSF on pulmonary DCs is influential in lymphocyte responses in the lung 25, 26. Treatment of epithelial cells with diesel exhaust particles, a major component of UPM, is known to stimulate production of GM‐CSF that in turn promotes DC maturation and activation 18.…”

Section: Introductionmentioning

confidence: 99%

Urban particulate matter stimulation of human dendritic cells enhances priming of naive CD8 T lymphocytes

Pfeffer

Mann

et al. 2017

Immunology

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SummaryEpidemiological studies have consistently shown associations between elevated concentrations of urban particulate matter (UPM) air pollution and exacerbations of asthma and chronic obstructive pulmonary disease, which are both associated with viral respiratory infections. The effects of UPM on dendritic cell (DC) ‐stimulated CD4 T lymphocytes have been investigated previously, but little work has focused on CD8 T‐lymphocyte responses despite their importance in anti‐viral immunity. To address this, we examined the effects of UPM on DC‐stimulated naive CD8 T‐cell responses. Expression of the maturation/activation markers CD83, CCR7, CD40 and MHC class I on human myeloid DCs (mDCs) was characterized by flow cytometry after stimulation with UPM in vitro in the presence/absence of granulocyte–macrophage colony‐stimulating factor (GM‐CSF). The capacity of these mDCs to stimulate naive CD8 T‐lymphocyte responses in allogeneic co‐culture was then assessed by measuring T‐cell cytokine secretion using cytometric bead array, and proliferation and frequency of interferon‐γ (IFN‐γ)‐producing T lymphocytes by flow cytometry. Treatment of mDCs with UPM increased expression of CD83 and CCR7, but not MHC class I. In allogeneic co‐cultures, UPM treatment of mDCs enhanced CD8 T‐cell proliferation and the frequency of IFN‐γ + cells. The secretion of tumour necrosis factor‐α, interleukin‐13, Granzyme A and Granzyme B were also increased. GM‐CSF alone, and in concert with UPM, enhanced many of these T‐cell functions. The PM‐induced increase in Granzyme A was confirmed in a human experimental diesel exposure study. These data demonstrate that UPM treatment of mDCs enhances priming of naive CD8 T lymphocytes and increases production of pro‐inflammatory cytokines. Such UPM‐induced stimulation of CD8 cells may potentiate T‐lymphocyte cytotoxic responses upon concurrent airway infection, increasing bystander damage to the airways.

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Alveolar epithelial cells orchestrate DC function in murine viral pneumonia

Cited by 97 publications

References 58 publications

GM-CSF–Licensed CD11b+ Lung Dendritic Cells Orchestrate Th2 Immunity to Blomia tropicalis

GM-CSF–Licensed CD11b+ Lung Dendritic Cells Orchestrate Th2 Immunity to Blomia tropicalis

Influenza virus-induced lung injury: pathogenesis and implications for treatment

Urban particulate matter stimulation of human dendritic cells enhances priming of naive CD8 T lymphocytes

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