The respiratory tract is continuously exposed to both innocuous airborne antigens and immunostimulatory molecules of microbial origin, such as LPS. At low concentrations, airborne LPS can induce a ...lung DC-driven Th2 cell response to harmless inhaled antigens, thereby promoting allergic asthma. However, only a small fraction of people exposed to environmental LPS develop allergic asthma. What prevents most people from mounting a lung DC-driven Th2 response upon exposure to LPS is not understood. Here we have shown that lung interstitial macrophages (IMs), a cell population with no previously described in vivo function, prevent induction of a Th2 response in mice challenged with LPS and an experimental harmless airborne antigen. IMs, but not alveolar macrophages, were found to produce high levels of IL-10 and to inhibit LPS-induced maturation and migration of DCs loaded with the experimental harmless airborne antigen in an IL-10-dependent manner. We further demonstrated that specific in vivo elimination of IMs led to overt asthmatic reactions to innocuous airborne antigens inhaled with low doses of LPS. This study has revealed a crucial role for IMs in maintaining immune homeostasis in the respiratory tract and provides an explanation for the paradox that although airborne LPS has the ability to promote the induction of Th2 responses by lung DCs, it does not provoke airway allergy under normal conditions.
Mast cell-derived group III phospholipase A
2
(PLA2G3) and fibroblast prostaglandin synthase contribute to a PGD
2
and mast-cell-DP-1-dependent mast cell-fibroblast paracrine axis that can enhance ...mast cell maturation and mediator secretion.
Air pollution, including particulates and gazes such as ozone (O
), is detrimental for patient's health and has repeatedly been correlated to increased morbidity and mortality in industrialised ...countries. Although studies have described a link between ambient particulate matter and increased lung cancer morbidity, no direct relation has yet been established between O
exposure and metastatic dissemination to lungs.
To outline the mechanisms through which pulmonary O
exposure modulates metastasis kinetics in an experimental mouse model of O
exposure.
Metastatic responses to pulmonary O
exposure were assessed using a reliable experimental mouse model of concomitant pulmonary O
exposure and tumour cell injection. Roles of neutrophils in O
-induced lung metastasis were highlighted using blocking anti-Ly6G antibodies; moreover, the implication of neutrophil extracellular traps (NETs) in metastatic processes was evaluated using
mice or by treating mice with DNase I.
Pulmonary O
exposure strongly facilitates the establishment of lung metastasis by (1) Inducing a pulmonary injury and neutrophilic inflammation, (2) Influencing very early steps of metastasis, (3) Priming neutrophils' phenotype to release NETs that favour tumour cell colonisation in lungs. The ability of O
-primed neutrophils to enhance lung colonisation by tumour cells was proven after their adoptive transfer in Balb/c mice unexposed to O
.
Pulmonary neutrophils induced by O
promote metastatic dissemination to lungs by producing NETs. These findings open new perspectives to improve treatment and prevention strategies in patients affected by metastatic diseases.
Lung macrophages constitute a sophisticated surveillance and defense system that contributes to tissue homeostasis and host defense and allows the host to cope with the myriad of insults and antigens ...to which the lung mucosa is exposed. As opposed to alveolar macrophages, lung interstitial macrophages (IMs) express high levels of Type 2 major histocompatibility complex (MHC-II), a hallmark of antigen-presenting cells. Here, we showed that lung IMs, like dendritic cells, possess the machinery to present soluble antigens in an MHC-II-restricted way. Using
ovalbumin (OVA)-specific T cell proliferation assays, we found that OVA-pulsed IMs could trigger OVA-specific CD4
T cell proliferation and Foxp3 expression through MHC-II-, IL-10-, and transforming growth factor β-dependent mechanisms. Moreover, we showed that IMs efficiently captured locally instilled antigens
, did not migrate to the draining lymph nodes, and enhanced local interactions with CD4
T cells in a model of OVA-induced allergic asthma. These results support that IMs can present antigens to CD4
T cells and trigger regulatory T cells, which might attenuate lung immune responses and have functional consequences for lung immunity and T cell-mediated disorders.
Background
In contrast to their clearly defined roles in allergic diseases, the physiologic functions of Immunoglobulin E antibodies (IgEs) and mast cells (MCs) remain enigmatic. Recent research ...supports the toxin hypothesis, showing that MCs and IgE‐related type 2 immune responses can enhance host defense against certain noxious substances, including honeybee venom (BV). However, the mechanisms by which MCs can interfere with BV toxicity are unknown. In this study, we assessed the role of IgE and certain MC products in MC‐mediated BV detoxification.
Methods
We applied in vitro and in vivo fluorescence microscopyimaging, and flow cytometry, fibroblast‐based toxicity assays and mass spectrometry to investigate IgE‐mediated detoxification of BV cytotoxicity by mouse and human MCs in vitro. Pharmacologic strategies to interfere with MC‐derived heparin and proteases helped to define the importance of specific detoxification mechanisms.
Results
Venom‐specific IgE increased the degranulation and cytokine responses of MCs to BV in vitro. Passive serum sensitization enhanced MC degranulation in vivo. IgE‐activated mouse or human MCs exhibited enhanced potential for detoxifying BV by both proteolytic degradation and heparin‐related interference with toxicity. Mediators released by IgE‐activated human MCs efficiently degraded multiple BV toxins.
Conclusions
Our results both reveal that IgE sensitization enhances the MC's ability to detoxify BV and also assign efficient toxin‐neutralizing activity to MC‐derived heparin and proteases. Our study thus highlights the potential importance of IgE, MCs, and particular MC products in defense against BV.
Immunoglobulin E antibodies increase mast cell responsiveness to honeybee venom in vitro and in vivo. Compounds released by IgE‐activated mouse and human mast cells can efficiently detoxify honeybee venom. Mast cell‐derived heparin and proteases contribute to prevention of honeybee venom toxicity
Objective
Gouty arthritis is caused by the precipitation of monosodium urate monohydrate (MSU) crystals in the joints. While it has been reported that mast cells (MCs) infiltrate gouty tophi, little ...is known about the actual roles of MCs during acute attacks of gout. This study was undertaken to assess the role of MCs in a mouse model of MSU crystal–induced acute arthritis.
Methods
We assessed the effects of intraarticular (IA) injection of MSU crystals in various strains of mice with constitutive or inducible MC deficiency or in mice lacking interleukin‐1β (IL‐1β) or other elements of innate immunity. We also assessed the response to IA injection of MSU crystals in genetically MC‐deficient mice after IA engraftment of wild‐type or IL‐1β–/– bone marrow–derived cultured MCs.
Results
MCs were found to augment acute tissue swelling following IA injection of MSU crystals in mice. IL‐1β production by MCs contributed importantly to MSU crystal–induced tissue swelling, particularly during its early stages. Selective depletion of synovial MCs was able to diminish MSU crystal–induced acute inflammation in the joints.
Conclusion
Our findings identify a previously unrecognized role of MCs and MC‐derived IL‐1β in the early stages of MSU crystal–induced acute arthritis in mice.
Very few transcription factors have been identified that are required by antigen-presenting cells (APCs) to induce T helper type 2 (Th2) responses. Because lung CD11b super(+) conventional dendritic ...cells (CD11b super(+) cDCs) are responsible for priming Th2 responses in house-dust mite (HDM)-induced airway allergy, we used them as a model to identify transcriptional events regulating the pro-Th2 activity of cDCs. Transcriptomic profiling of lung CD11b super(+) cDCs exposed to HDM in vivo revealed first that HDM triggers an antiviral defence-like response, and second that the majority of HDM-induced transcriptional changes depend on the transcription factor Interferon Response Factor-3 (Irf3). Validating the functional relevance of these observations, Irf3-deficient CD11b super(+) cDCs displayed reduced pro-allergic activity. Indeed, Irf3-deficient CD11b super(+) cDCs induced less Th2, more regulatory T cell, and similar Th1 differentiation in naive CD4 super(+) T cells compared to their wild-type counterparts. The altered APC activity of Irf3 CD11b super(+) cDCs was associated with reduced expression of CD86 and was phenocopied by blocking CD86 activity in wild-type CD11b super(+) cDCs. Altogether, these results establish Irf3, known mostly for its role in antiviral responses, as a transcription factor involved in the induction of Th2 responses through the promotion of pro-Th2 costimulation in CD11b super(+) DCs. House dust mite triggers an Irf3-dependent antiviral-like transcriptional program in lung resident type 2 conventional dendritic cells. This program promotes Th2 responses by increasing CD86 gene expression and hence CD86 costimulation. .
Very few transcription factors have been identified that are required by antigen‐presenting cells (APCs) to induce T helper type 2 (Th2) responses. Because lung CD11b+ conventional dendritic cells ...(CD11b+ cDCs) are responsible for priming Th2 responses in house‐dust mite (HDM)‐induced airway allergy, we used them as a model to identify transcriptional events regulating the pro‐Th2 activity of cDCs. Transcriptomic profiling of lung CD11b+ cDCs exposed to HDM in vivo revealed first that HDM triggers an antiviral defence‐like response, and second that the majority of HDM‐induced transcriptional changes depend on the transcription factor Interferon Response Factor‐3 (Irf3). Validating the functional relevance of these observations, Irf3‐deficient CD11b+ cDCs displayed reduced pro‐allergic activity. Indeed, Irf3‐deficient CD11b+ cDCs induced less Th2, more regulatory T cell, and similar Th1 differentiation in naïve CD4+ T cells compared to their wild‐type counterparts. The altered APC activity of Irf3 CD11b+ cDCs was associated with reduced expression of CD86 and was phenocopied by blocking CD86 activity in wild‐type CD11b+ cDCs. Altogether, these results establish Irf3, known mostly for its role in antiviral responses, as a transcription factor involved in the induction of Th2 responses through the promotion of pro‐Th2 costimulation in CD11b+ DCs.
House dust mite triggers an Irf3‐dependent antiviral‐like transcriptional program in lung resident type 2 conventional dendritic cells. This program promotes Th2 responses by increasing CD86 gene expression and hence CD86 costimulation.
.
Background Type 2 cytokine-related immune responses associated with development of antigen-specific IgE antibodies can contribute to pathology in patients with allergic diseases and to fatal ...anaphylaxis. However, recent findings in mice indicate that IgE also can enhance defense against honeybee venom. Objective We tested whether IgE antibodies, IgE-dependent effector mechanisms, and a local anaphylactic reaction to an unrelated antigen can enhance defense against Russell viper venom (RVV) and determined whether such responses can be influenced by immunization protocol or mouse strain. Methods We compared the resistance of RVV-immunized wild-type, IgE-deficient, andFcer1a-deficient mice after injection of a potentially lethal dose of RVV. Results A single prior exposure to RVV enhanced the ability of wild-type mice, but not mice lacking IgE or functional Fc(epsilon)RI, to survive challenge with a potentially lethal amount of RVV. Moreover, IgE-dependent local passive cutaneous anaphylaxis in response to challenge with an antigen not naturally present in RVV significantly enhanced resistance to the venom. Finally, we observed different effects on resistance to RVV or honeybee venom in BALB/c versus C57BL/6 mice that had received a second exposure to that venom before challenge with a high dose of that venom. Conclusion These observations illustrate the potential benefit of IgE-dependent effector mechanisms in acquired host defense against venoms. The extent to which type 2 immune responses against venoms can decrease pathology associated with envenomation seems to be influenced by the type of venom, the frequency of venom exposure, and the genetic background of the host.
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