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Role of dysregulated RNA-interfaces in systemic immune system failure

Malfunctions of the immune system can trigger life-threatening conditions, accounting for millions of death cases annually. Examples are inflammatory processes during coronary heart disease, autoimmune-diseases or misguided immune reactions in the context of systemic inflammatory response-syndrome (SIRS). The latter may develop upon acute pancreatitis, trauma or major surgery. SIRS may also develop in the form of sepsis, even when the causative agent has been cleared with antibiotics. Thus, while SIRS can have multiple triggers, a misguided immune response is the common denominator. Despite the high number of cases and mortality, the molecular drivers of SIRS remain insufficiently understood, impeding the development of urgently needed novel therapeutic angles.

This project builds upon preliminary work, which revealed a novel immuno-suppressive RNA-binding complex dysregulated under SIRS conditions. Using state-of-the-art quantitative proteomics, RNA-seq and classical RNA biochemistry, we found that maturation of this complex depends on nuclear speckles and that its down-regulation in SIRS patients and in in vitro activated phagocytes is a consequence of c-Myc repression. Intriguingly, silencing of this c-Myc dependent RNA-complex in resting phagocytes spontaneously activated type-I interferon and interferon-stimulated gene (ISG) expression, suggesting an important role in inflammation control. Through dissection of the precise mechanism of action of this RNA-guided immune-suppressor complex, we strive to improve our molecular understanding of dysregulated phagocyte immunity in SIRS and provide new angles for patient stratification and treatment.

Known roles of lncRNAs in murine (green) and human (blue) phagocyte innate immune signalling.
The TLR4 and RIG-I pathways are shown exemplarily, with lncRNAs involved in the MyD88-NFkB, the TRIF-IRF3 and the MAVS-IRF3 signalling arm indicated.
Source: Walther & Schulte, RNA Biology 2021.