Programmierung von alveolaren Makrophagen durch mRNA-Abbau

regulated by mRNA decay. AMs are tissue-resident macrophages indispensable for the functional integrity of
the lung. They drive a wide range of fundamental processes such as responses to pathogens, lung tissue
homeostasis and regeneration, and metabolic adaptations. Moreover, they help maintain a heathy balance
between inflammatory and tolerogenic programs. The remarkable functional plasticity of AMs depends on
the rapid reprogramming of their transcriptome in response to microenvironmental cues. Recent advances
have revealed important roles for transcription factors and epigenetic mechanisms in AM development and
identity. However, these findings also highlight knowledge gaps in the mechanisms underlying the flexible
and dynamic behavior of AMs within the tissue niche. Importantly, the role of mRNA decay in regulating AMs
—and tissue-resident macrophages in general—has not yet been explored.
Hypotheses / research questions / objectives:
Our preliminary data on AMs deficient in the mRNA-destabilizing protein tristetraprolin (TTP, gene name
Zfp36) indicate that mRNA decay is a key determinant of AM programming. TTP is an essential anti-
inflammatory RNA-binding protein (RBP) that regulates the expression of inflammation-associated genes,
such as cytokines and chemokines. Our cell-based and animal studies suggest that TTP integrates
microenvironmental cues to program AMs and the AM ability to orchestrate defense against bacterial lung
infection and protection against acute lung injury. The major objectives of the project are to (i) define the
(re)programming of AMs by TTP-mediated mRNA decay, (ii) determine whether TTP instructs AMs during
their development or in the lung tissue niche, and (iii) elucidate how TTP controls the host-protective
functions of AMs during lung infection and lung tissue injury.
Approach / Methods: The project will employ in vivo, ex vivo and in vitro approaches including AM
transplantation, lung transcriptomics at single cell level, tissue-specific TTP deletion, inducible TTP deletion
in AMs ex vivo, SLAM-seq for mRNA stability assays and APEX-seq for RNA-protein interaction studies in
AMs. Animal experiments will employ models of bacterial lung infection and acute lung injury.
Level of originality / innovation:
The project represents a pioneering effort to investigate AM regulation by mRNA decay. The experimental
approach includes several methodologies—such as mRNA decay analysis and RNA-protein interaction
studies—that will be applied to AMs for the first time. The results are expected to stimulate the largely
underexplored field of resident macrophage programming by mRNA decay, extending beyond TTP and AMs.
Primary researchers involved: Pavel Kovarik (principal investigator & applicant)