Origin, Localization, and Immunoregulatory Properties of Pulmonary Phagocytes in Allergic Asthma

Franziska Hoffmann, Fanny Ender, Inken Schmudde, Ian P. Lewkowich, Jörg Köhl, Peter König, Yves Laumonnier

Allergic asthma is a chronic inflammatory disease of the airways that is driven by maladaptive T helper 2 (Th2) and Th17 immune responses against harmless, airborne substances. Pulmonary phagocytes represent the first line of defense in the lung where they constantly sense the local environment for potential threats. They comprise two distinct cell types, i.e., macrophages and dendritic cells (DC) that differ in their origins and functions. Alveolar macrophages quickly take up most of the inhaled allergens, yet do not deliver their cargo to naive T cells sampling in draining lymph nodes. In contrast, pulmonary DCs instruct CD4(+) T cells develop into Th2 and Th17 effectors, initiating the maladaptive immune responses toward harmless environmental substances observed in allergic individuals. Unraveling the mechanisms underlying this mistaken identity of harmless, airborne substances by innate immune cells is one of the great challenges in asthma research. The identification of different pulmonary DC subsets, their role in antigen uptake, migration to the draining lymph nodes, and their potential to instruct distinct T cell responses has set the stage to unravel this mystery. However, at this point, a detailed understanding of the spatiotemporal resolution of DC subset localization, allergen uptake, processing, autocrine and paracrine cellular crosstalk, and the humoral factors that define the activation status of DCs is still lacking. In addition to DCs, at least two distinct macrophage populations have been identified in the lung that are either located in the airway/alveolar lumen or in the interstitium. Recent data suggest that such populations can exert either pro- or anti-inflammatory functions. Similar to the DC subsets, detailed insights into the individual roles of alveolar and interstitial macrophages during the different phases of asthma development are still missing. Here, we will provide an update on the current understanding of the origin, localization, and function of the diverse pulmonary antigen-presenting cell subsets, in particular with regard to the development and regulation of allergic asthma. While most data are from mouse models of experimental asthma, we have also included available human data to judge the translational value of the findings obtained in experimental asthma models.