mRNA decay-driven control of neutrophils by macrophages

Homeostasis within the immune system is maintained by numerous regulatory mechanisms and involves diverse cellular players. This homeostasis balances the immune system under physiological conditions and governs specific responses after a challenge with infecting agents aiming at restoring homeostasis. If this balance is disrupted by insufficient or exaggerated immune reactions, pathological conditions develop which may lead to life-threatening diseases such as severe infections, toxic shock or autoimmune disorders. Thus, the understanding of the molecular mechanisms governing immune response is critical to the development of drug therapies that aim to alleviate or prevent such immune disorders and restore immune homeostasis. The proposed project will study how mRNA decay regulates interactions between neutrophils and macrophages such that immune cell homeostasis is maintained. Neutrophils and macrophages are key immune cells in defense against infections but also in orchestrating wound healing and recovery of the infected host. mRNA decay mediated the mRNA-binding and destabilizing protein tristetraprolin (TTP) has been known to restrict immune responses by limiting the abundance of inflammatory mRNAs. Consistently, studies had shown that its deletion causes spontaneous inflammation in mice. Our own data show that deletion of TTP specifically in neutrophils results in a similar phenotype. Surprisingly, mice lacking TTP in both neutrophils and macrophages are healthy suggesting that TTP-deficient macrophages counteract the neutrophil-driven inflammation in these mice. Thus, the key scientific question is how the lacking TTP- mediated mRNA decay in macrophages generates anti-inflammatory effects. To understand the mechanism of inflammatory disease in mice lacking TTP in neutrophils and the lack of such disease in mice lacking TTP in both neutrophils and macrophages an in-depth characterization of the mice will be performed in the first place. Then, we will investigate how TTP deletion enhances the anti-inflammatory and immunomodulatory properties of macrophages. Since the metabolic properties and macrophage polarization status are key determinants of macrophage function, their regulation by TTP-dependent mRNA decay will be characterized in the course of the project. Together, the proposed project will improve our understanding of the regulation of immune homeostasis by deciphering mRNA decay-controlled interactions between neutrophils and macrophages.

Homeostasis balances the immune system under physiological conditions and governs specific responses to challenges with infecting agents, thereby maintaining the immune system in check. This tightly regulated process involves several cellular players and is crucial to prevent pathological conditions arising either from insufficient or exaggerated immune reactions. In the recent years many of the pro- and anti-inflammatory processes have been identified, though the question of how these processes are coordinated in the context of balanced tissue-protective immune responses remains poorly understood. Besides cell-intrinsic processes, the inter-cellular crosstalk is an essential component of balanced immune response. This project investigated the role of the mRNA-destabilizing protein tristetraprolin (TTP) in the regulation of immune cell homeostasis by different subsets of myeloid cells. Specifically, the TTP-controlled interactions between neutrophils and macrophages have been investigated under steady state conditions and after an inflammatory challenge. TTP promotes the degradation of inflammation-associated mRNAs acting as an anti-inflammatory factor. Our data show that deletion of TTP specifically in neutrophils results in spontaneous inflammation in mice. Surprisingly, mice lacking TTP in both neutrophils and macrophages are healthy suggesting that TTP-deficient macrophages counteract the neutrophil-driven inflammation in these mice. In this project, TTP was identified as a driver of macrophage transcriptome, particularly in tissue resident macrophages and responsible for maintaining high oxidative respiratory capacity. This TTP-driven program occurs under homeostatic conditions but it is inhibited upon immunostimulation, in contrast to TTP function in neutrophils. Together the data imply a critical role of TTP in the ability of resident macrophages to control damage caused by neutrophils. The results of this project improved the understanding of the regulation of immune homeostasis by cellular and molecular crosstalk among myeloid cells. This study identified previously undiscovered distinct roles of TTP in macrophages and neutrophils, thereby contributing to the advance of the field.