Taming IL-1 signaling by mRNA decay

Defense against microbial pathogens requires an appropriate activation of the immune response and efficient brakes to inactivate the response once the pathogen is defeated. The activation of the immune system is accomplished by proteins termed cytokines which are secreted from cells that detect the pathogen. The cytokines of the IL-1 family are exceptionally powerful activators of the immune response. IL-1 cytokines can cause hyperactivation of the immune system leading to severe tissue or organ damage. Dysregulated IL-1 production is implicated in a number of human diseases including non- resolving inflammation, neurodegeneration and cancer. To avoid such deleterious effects, the production of IL-1 cytokines is under a strict multilayered control. The majority of recent studies focused on IL-1 regulation by protein processing and secretion, whereas little is known about the role of IL-1 mRNA decay. mRNA decay is a fundamental mechanism of regulated gene expression and represents a critical brake to stop the immune system activation. However, it remains unclear whether and how the degradation of IL-1 mRNA impacts the immune response and the entire organism. The proposed project will provide answers to these important questions by combining innovative biochemical approaches with immunobiology. The project revolves around the mRNA-binding protein tristetraprolin (TTP) which is known to promote degradation of many mRNAs induced during an immune response. Consequently, TTP has robust anti- inflammatory properties and it represents a major dampener of the immune response. We have obtained strong evidence that TTP is important for the degradation of IL-1 mRNA and that this degradation is essential for health. Intriguingly, this vital function of TTP is cell type- dependent as IL-1 mRNA is degraded by TTP only in a subset of immune cells. The major aim of the research project is to identify molecular mechanisms of how TTP destabilizes IL-1 mRNA and how this is achieved in a cell type-specific way. The approach will employ proteomics as a means for characterization of proteins regulating together with TTP the decay of IL-1 mRNA. The project results will provide mechanistic and functional insights into IL-1 regulation by mRNA decay. The findings will have therapeutic implications for IL-1- dependent diseases.

Interleukin 1 alpha (IL-1alpha) and Interleukin 1 beta (IL-1beta ) are signaling molecules that regulate inflammation and immunity in response to infection. They bind to the same receptor and were previously thought to be redundant. IL-1beta and IL-1beta are highly conserved in mammals, but have limited similarity with each other. Given that they bind the same receptor, and based on previous studies, it was anticipated that they have similar functions. The project revealed that IL-1alpha and IL-1beta exhibit tissue-specific expression patterns and have distinct functions in the defense against bacterial infections. Whereas IL-1beta drives bacterial clearance and hence resistance, IL-1alpha promotes host defense driving tolerance to infections. Both resistance and tolerance are essential for successful defense against infections. The project results have broad implications since the experiments employed two infection models: skin infection with Streptococcus pyogenes and lung infection with Streptococcus pneumoniae. Both pathogens are important infection agents in humans. Detailed analysis revealed that IL-1beta is essential for boosting the the production of neutrophils, i.e. leukocytes which are critically involved in the elimination of the pathogen. IL-1alpha, on the other hand, is dispensable for this process, but fine-tunes the immune response in the liver which is known to be a central hub for metabolic processes. Consistently, the data demonstrated that IL-1alpha reprograms liver metabolic pathways during infection. The project results further substantiated the awareness of the importance of IL-1alpha and IL-1beta regulation since insufficient or exaggerated levels of these two cytokines might cause disease. The IL-1alpha and IL-1beta production is regulated at multiple levels which include transcription and protein processing. The project discovered a new type of IL-1alpha and IL-1beta regulation, namely the regulation at the level of stability of mRNAs for these cytokines. The project provides evidence that the mRNAs for IL-1alpha and IL-1beta are targeted by the mRNA-destabilizing protein TTP. The TTP-mediated degradation of IL-1alpha and IL-1beta mRNAs is essential for the maintenance of immune homeostasis, and a failure in such degradation results in a severe inflammatory condition in multiple organs. The project findings enrich our knowledge about processes that precisely balance the activity of the immune system.