Project Details
Projekt
Alveolar macrophage self-renewal and type 2 immune response in lung injury
Applicant
Professor Dr. Michael Sieweke
Subject Area
Immunology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 322359157
Type 2 immune reactions play an important role in the lung and are of major clinical significance for conditions like asthma, lung infections, lung injury and fibrosis. Alveolar macrophages (AM) are resident macrophages of lung alveoli, which assume important homeostatic and immune modulatory functions. Alveolar macrophages are also important target and effector cells of type 2 immune reactions. In contrast to other macrophage populations, AM type 2 immune responses follow a distinct pattern, for which the underlying mechanisms are only poorly understood. The study of M2 polarization in these cells is therefore of high value for the understanding of type 2 immune responses in general. The lung has a strong regenerative capacity, where type 2 immune responses play an important role. Directly after birth the lung undergoes developmental changes characterized by alveolarization leading to massive increase of the gas exchange surface. After serious tissue injury the process of neo-alveolarization can be re-activated to compensate lost lung tissue. Both normal development and regeneration depend on the stimulation of type 2 immune responses in alveolar macrophages. This repair process becomes less effective with age or can be aberrant after massive tissue destruction during severe viral infections or other insults when excessive inflammation or fibrosis become dominant. Our previous work demonstrated that AM have intrinsic long-term self-renewal capacity that depends on low levels of the transcription factors MafB and c-Maf. In bone marrow derived macrophages and monocytes these transcription factors are also involved in type 2 polarization. Similarly, cytokines such as Il-4 have been shown to to not only regulate type polarization but also macrophage proliferation. We therefore want to investigate the link between self-renewal and type 2 polarization in AM. In contrast to juvenile, adult AM are refractory to type 2 stimulation. With age or in pathological conditions AM also loose self-renewal capacity.We hypothesize that successful regeneration requires both the competence of AM to mount an M2 response and to maintain self-renewal, whereas recruitment of inflammatory M1 polarized monocyte-derived macrophages causes aberrant repair process. We therefore want to explore mechanisms that allow to re-activate juvenile competence for self-renewal and M2 responsiveness to enhance the regenerative capacities of AM in lung injury and prevent pathological repair process. We will employ different conditions in culture and in vivo and single cell analysis to identify molecular signatures of self-renewal and M2 response competent AM. To validate our molecular findings in vivo, we will analyze whether mouse models with AM specific deletions of the self-renewal restricting factors MafB and Maf show alterations in M2 response dependent lung repair processes.
DFG Programme
Research Units
