Final Report Summary - DC IN ASTHMA (The impact of asthma on dendritic cell development; analysis at the cellular and the molecular level)
The incidence of allergic diseases, including allergic asthma, is steadily increasing in westernized countries, causing a heavy individual and socioeconomic burden on society. In some European countries, almost one third of all children has features of allergic asthma, allergic rhinitis or atopic dermatitis. Novel forms of prevention and/or cure of allergic diseases are therefore urgently needed, necessitating further research in the basic mechanisms of immune activation. The development of allergic asthma requires the activity of a specific immune cells, namely dendritic cells (DCs). Novel asthma therapies could involve interference with the development and relative abundance of functionally specialized lung DC subsets.
Asthma drastically changes the absolute and relative abundance of lung DC subsets including CD103+ conventional DCs (cDCs), CD11b+ cDCs, monocyte-derived DCs and plasmacytoid DCs. This project aimed to investigate the hypothesis that DC progenitor/precursor development, selection and differentiation choices are affected by allergen-induced airway inflammation. The project was started by comparing the distribution of bone marrow, splenic and circulating DC progenitors and precursors in healthy and asthmatic mice. Experiments were divided into three categories, analyzing mice in which an early response to the allergen house dust mite (HDM) was induced, mice that had developed full-blown asthma and mice suffering from chronic asthma. Analysis of DC subsets in lung, broncho-alveolar lavage and lymph nodes confirmed previously published findings that CD11b+ cDCs and monocyte-derived DCs increase following HDM exposure (Plantinga et al, Immunity, 2013). However, no robust changes were found in the proportions or absolute numbers of progenitor/precursor cells in HDM-exposed or asthmatic mice. In addition, no imprinting effect of lung HDM-exposure on in vitro bone marrow-derived DC differentiation capacity could be shown. To identify cytokines and molecular mechanisms involved in the skewing of DC differentiation, we added candidate factors to Flt3L or GM-CSF bone marrow DC cultures. Interestingly, many of the in vivo effects of HDM-exposure/asthma observed in mice could be replicated by addition of asthma-associated cytokines/factors to bone marrow DC cultures. However, the fact that in vivo experiments have not demonstrated clear differences between the DC progenitors and precursors suggests that these changes occur relatively late in the DC developmental process, for example in the lung tissue. Interestingly, a recently published study shows that Toxoplasma gondii infection can affect monocyte differentiation in the bone marrow (Askenase et al, Immunity, 2015), showing that changes in early bone marrow progenitors can be induced by some severe infection models. However, in the case of asthma such a systemic effect appears absent. Thus, involvement of the bone marrow may be dependent on the type of inflammation. Together, the findings of this project show no evidence for early developmental changes in DC progenitor/precursor distribution and differentiation choices in asthma. The changes in DC subset numbers and distribution therefore need to be explained by an alternative hypothesis, such as altered local migration and/or in-tissue differentiation and activation of specific DC subsets. By excluding an impact of early developmental choices, the data obtained in this project show that interference with early DC progenitors/precursors to treat the relative abundance of functionally specialized lung DC subsets is not the way to go for the development of novel asthma therapies.
As the data suggested that changes in DC development during asthma were dependent on local lung signals rather than on changes in bone marrow progenitors, the project was slightly reoriented to understand how the lung environment imprints the fate of myeloid precursor cells. Three different precursors were compared with regard to their capacity to develop into lung-resident macrophages. This study (van de Laar et al, Immunity, In press) confirmed the hypothesis that imprinting by local factors is the main factor controlling the fate of lung-resident macrophages. These findings show that precursor cells, including relatively easily accessible blood monocytes, could potentially be applied for cellular therapy in diseases where functional tissue macrophages are lost or dysfunctional.
Contact details:
Prof. B.N. Lambrecht, Immunoregulation and mucosal immunology, Inflammation Research Center, VIB-UGhent, Ghent, Belgium, bart.lambrecht@irc.vib-ugent.be
Asthma drastically changes the absolute and relative abundance of lung DC subsets including CD103+ conventional DCs (cDCs), CD11b+ cDCs, monocyte-derived DCs and plasmacytoid DCs. This project aimed to investigate the hypothesis that DC progenitor/precursor development, selection and differentiation choices are affected by allergen-induced airway inflammation. The project was started by comparing the distribution of bone marrow, splenic and circulating DC progenitors and precursors in healthy and asthmatic mice. Experiments were divided into three categories, analyzing mice in which an early response to the allergen house dust mite (HDM) was induced, mice that had developed full-blown asthma and mice suffering from chronic asthma. Analysis of DC subsets in lung, broncho-alveolar lavage and lymph nodes confirmed previously published findings that CD11b+ cDCs and monocyte-derived DCs increase following HDM exposure (Plantinga et al, Immunity, 2013). However, no robust changes were found in the proportions or absolute numbers of progenitor/precursor cells in HDM-exposed or asthmatic mice. In addition, no imprinting effect of lung HDM-exposure on in vitro bone marrow-derived DC differentiation capacity could be shown. To identify cytokines and molecular mechanisms involved in the skewing of DC differentiation, we added candidate factors to Flt3L or GM-CSF bone marrow DC cultures. Interestingly, many of the in vivo effects of HDM-exposure/asthma observed in mice could be replicated by addition of asthma-associated cytokines/factors to bone marrow DC cultures. However, the fact that in vivo experiments have not demonstrated clear differences between the DC progenitors and precursors suggests that these changes occur relatively late in the DC developmental process, for example in the lung tissue. Interestingly, a recently published study shows that Toxoplasma gondii infection can affect monocyte differentiation in the bone marrow (Askenase et al, Immunity, 2015), showing that changes in early bone marrow progenitors can be induced by some severe infection models. However, in the case of asthma such a systemic effect appears absent. Thus, involvement of the bone marrow may be dependent on the type of inflammation. Together, the findings of this project show no evidence for early developmental changes in DC progenitor/precursor distribution and differentiation choices in asthma. The changes in DC subset numbers and distribution therefore need to be explained by an alternative hypothesis, such as altered local migration and/or in-tissue differentiation and activation of specific DC subsets. By excluding an impact of early developmental choices, the data obtained in this project show that interference with early DC progenitors/precursors to treat the relative abundance of functionally specialized lung DC subsets is not the way to go for the development of novel asthma therapies.
As the data suggested that changes in DC development during asthma were dependent on local lung signals rather than on changes in bone marrow progenitors, the project was slightly reoriented to understand how the lung environment imprints the fate of myeloid precursor cells. Three different precursors were compared with regard to their capacity to develop into lung-resident macrophages. This study (van de Laar et al, Immunity, In press) confirmed the hypothesis that imprinting by local factors is the main factor controlling the fate of lung-resident macrophages. These findings show that precursor cells, including relatively easily accessible blood monocytes, could potentially be applied for cellular therapy in diseases where functional tissue macrophages are lost or dysfunctional.
Contact details:
Prof. B.N. Lambrecht, Immunoregulation and mucosal immunology, Inflammation Research Center, VIB-UGhent, Ghent, Belgium, bart.lambrecht@irc.vib-ugent.be