The innate immune brakes of the lung

Respiratory mucosal surfaces are continuously exposed to not only innocuous non-self antigens but also pathogen-associated molecular patterns (PAMPs) originating from environmental or symbiotic microbes. According to either “self/non-self” or “danger” models, this should systematically result in homeostasis breakdown and the development of immune responses directed to inhaled harmless antigens, such as T helper type (Th)2-mediated asthmatic reactions, which is fortunately not the case in most people. This discrepancy implies the existence, in the lung, of regulatory mechanisms that tightly control immune homeostasis. Although such mechanisms have been poorly investigated in comparison to the ones that trigger immune responses, a better understanding of them could be useful in the development of new therapeutic strategies against lung diseases (e.g., asthma). Here, we review current knowledge on innate immune cells that prevent the development of aberrant immune responses in the lung, thereby contributing to mucosal homeostasis

Resident CD11b(+)Ly6C(-) Lung Dendritic Cells Are Responsible for Allergic Airway Sensitization to House Dust Mite in Mice.

peer reviewedConventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway sensitization. Here, we systematically assessed the respective pro-allergic potential of individually sorted lung DC subsets isolated from house dust mite antigen (HDM)-treated donor mice, following transfer to naive recipients. Transfer of lung CD11c(+)CD11b(+) DCs, but not CD11c(+)CD11b(-)CD103(+) DCs, was sufficient to prime airway allergy. The CD11c(+)CD11b(+) DC subpopulation was composed of CD11c(+)CD11b(+)Ly6C(+) inflammatory monocyte-derived cells, whose numbers increase in the lungs following HDM exposure, and of CD11c(+)CD11b(+)Ly6C(-) DCs, which remain stable. Counterintuitively, only CD11c(+)CD11b(+)Ly6C(-) DCs, and not CD11c(+)CD11b(+)Ly6C(+) DCs, were able to convey antigen to the lymph nodes and induce adaptive T cell responses and subsequent airway allergy. Our results thus support that lung resident non-inflammatory CD11c(+)CD11b(+)Ly6C(-) DCs are the essential inducers of allergic airway sensitization to the common aeroallergen HDM in mice

University population-based prospective cohort study of SARS-CoV- 2 infection and immunity (SARSSURV-ULiège): a study protocol

peer reviewe

Ontogenic, phenotypic and functional characterization of lung interstitial macrophages after exposure to bacterial compounds

Respiratory mucosal surfaces are continuously exposed to harmless antigens and immunostimulatory molecules of microbial origin. According to the « self/non self » and « danger » theories, this should normally result in the developpment of unwanted immune responses towards these inhaled antigens such as Th2-mediated allergic responses. This is however not the case in most people. The hygiene hypothesis postulates that living in an environment rich in microbial components paradoxically protects from airway allergy, implying the existence in the lung of suppressive mechanisms triggered by these immunogenic signals. In this study, we showed that synthetic bacterial DNA rich in unmethylated CpG motifs (CpG) has the unique ability to significantly increase the population of lung interstitial regulatory macrophages (IM) from CCR2-independent monocytes residing in the lung or mobilized from the spleen. Moreover these CpG-induced IM demonstrated a hypersuppressive profile as they produced more IL-10 than their steady state counterparts. Using mice models of airway allergy we showed that the transfert of IM isolated from CpG-treated mice recapitulated the protective effects of CpG when administered before allergen sensitization or challenge. This IM-mediated protection was dependant from IL-10 as CpG-induced Il10-/- IM had no protective effect. The expansion of pulmonary regulatory IM from CCR2-independent pulmonary and splenic monocytes upon CpG exposure could be a possible mechanism by which exposure to an environment rich in microbial products protects against asthma.Etude des mécanismes suppresseurs au niveau de la muqueuse pulmonair

Release of Neutrophils Extracellular Traps as a main trigger for asthma onset

Allergic asthma is an important Th2 associated immunopathology. Even if the pathology of the disease is well described, its etiology is still largely unknown. Nevertheless, some environmental factors like viral infections and exposition to low doses of lipopolysaccharide (LPS) strongly increase the risk of disease inception. Interestingly, these two particular risk factors both induce a strong recruitment of neutrophils into the lung. Recently, scientists highlighted the ability of neutrophils to form neutrophils extracellular traps (NETs) composed of a network of extracellular DNA associated to anti-microbial peptides. NETs release (or NETosis) is an important component in organism defence against pathogen invasion but has also been identified as initiator of pathophysiological conditions like erythematous systemic lupus, gout and diabetes. In this study, we investigated the role of NETs as potential asthma inducers in specific pro-Th2 environmental risk factors like respiratory viral infections and low LPS doses exposures (also known as hygiene hypothesis). First, we assessed the correlation between respiratory viral infection or low LPS exposure and NETosis using western blot and confocal microscopy analysis. An influenza A infection induced a strong NETs release between day three and seven after viral inoculation whereas exposition to low (100 ng LPS) but not to high (10 µg LPS) LPS doses also promoted NETosis within 24 hours following the exposition. Then we developed two mouse models, a virus-induced asthma model and a model of asthma promoted by exposition to low LPS doses. In these models, only previously infected mice or mice exposed to low LPS doses displayed all the characteristics of allergic asthma following sensitization and challenge to house dust mite (HDM). The role of NETs in asthma onset was then demonstrated using three NETosis inhibitors (DNAse, Cl-amidine and inhibitor of neutrophil elastase) in our models as infected or low LPS doses exposed mice exhibited strong decreased of all key asthma features when treated with NETs inhibitors compared to non-treated mice. Finally, to address how NETs could lead to a TH2 immune response, we analysed by flow cytometry the distinct subpopulations of lung dendritic cells (DCs) in our two mice models. We observed, during the NETs release phase, a recruitment of monocytic derived DCs (moDCs). In conclusion, we have demonstrated an unexpected role for NETs in asthma onset by recruiting lung moDCs

Procédés de différenciation in vitro de monocytes en macrophages régulateurs

publication date: 2017-03-09; filing date: 2018-09-1

Resident CD11b+Ly6C-, not neo-recruited inflammatory CD11b+Ly6C+ dendritic cells mediate allergic airway sensitization to house dust mite antigens

peer reviewe

Resident non inflammatory CD11b+ lung dendritic cells are responsible for allergic airway sensitization to house dust mite in mice.

peer reviewe