Distinct functions of IL-1a versus IL-1ß in host defense

Our immune system protects us efficiently against pathogens we are exposed to on a daily basis. Protection against infection is mediated by both resistance against the pathogen and tolerance to the disease. Resistance mechanisms drive the elimination of the pathogen, while tolerance mechanisms limit tissue damage and restore organ functions. Upon infection, the immune system employs signaling proteins termed cytokines to activate immune responses as well as resistance and tolerance mechanisms. The cytokines IL-1 and IL-1 are involved in the majority of physiological and pathological inflammatory conditions but their individual functions remain poorly understood. IL-1a and IL-1ß use the same receptor and elicit same cellular responses. This raises the basic question as to why both cytokines are pre sent in mammals: does each of these cytokines accomplish unique and indispensable functions or are they redundant? Answering these questions has proven difficult due to the challenges with establishing models suitable for the assessment of IL-1a versus IL-1ß functions. We were able to overcome these challenges and found out that IL-1a and IL-1ß are not redundant, and have distinct functions in the context of bacterial infections. IL-1a governed tolerance to infection, while IL-1ß function was essential for resistance. The proposed project will investigate the precise mechanisms underlying the different functions of IL-1a and IL-1ß in host defense. The studies will employ models of infection with important pathogens Streptococcus pyogenes and Streptococcus pneumoniae that cause invasive infections of the soft tissue and pneumonia, respectively. The investigations will focus on regulation of metabolism which is subject to massive adaptations during infection. Failures in these metabolic adjustments decrease the ability of launching a successful defense against the pathogen. The findings of the proposed project are likely to have broad implications for therapies of infectious diseases.

Inflammation is a natural response by which cells and organisms activate defense against infections and environmental insults. However, inflammation must be resolved for successful healing. Uncontrolled inflammation can result in pathologies ranging from organ damage to autoimmune diseases and cancer. The project funded by the FWF discovered a mechanism that is indispensable for safeguarding efficient immune response and preventing damaging hyperinflammation. The mechanism includes a fate decision step that orchestrates the degradation of mRNAs (messenger RNAs) encoding inflammation-promoting cytokines. The key player in this novel mechanism is the anti-inflammatory mRNA-destabilizing protein tristetraprolin (TTP). TTP binds to mRNAs encoding inflammation-promoting mRNAs such as cytokine mRNAs and promotes their degradation. This way, inflammation is terminated, and the healing process can start. Data obtained from model systems provide evidence that TTP is essential for balanced immune responses against pathogens and for the maintenance of healthy immune environment. The lack of this protein results in a severe multi-organ inflammation. However, how the unprecedently efficient control of immune responses by TTP is brought about has remained elusive. The results of the project revealed that TTP regulates the degradation of target mRNAs, such as cytokine mRNAs, in the nucleus, rather than in the cytoplasm where the actual decay occurs. This way, the target mRNAs are marked for degradation already early in the RNA life cycle so that no protein from these mRNAs can be produced during translation. A central part of the mechanism is that the TTP binds pre-mRNA in the cell nucleus, not mature mRNA in the cytoplasm. The project data further suggest that this nuclear licensing mechanism is relevant also