DFG TRR156/2 B05 SFB Transregio "Dual roles of RNA-induced immune activation in the skin"

01.07.2019 bis 30.06.2023

Bacterial and host RNA have emerged as vital and underestimated stimuli for the activation of innate immunity in macrophages and dendritic cells but also in keratinocytes and, as shown in the previous funding period, polymorphonuclear neutrophils (PMNs). Interestingly, RNA sensing via endosomal Toll-like receptors (TLRs) in the skin context appears to have dual – i.e. beneficial as well as detrimental – innate and possibly adaptive immune outcomes. As such, TLR8/13 RNA recognition of microbial RNA was identified by the Eigenbrod group as critical for limiting skin infections with Streptococcus pyogenes, a human pathogen causing a variety of diseases including life-threatening skin and soft tissue infections. On the other hand, in the context of psoriasis, the Weber group observed that both host and bacterial RNA complexed to the antimicrobial peptide and psoriasis autoantigen, LL37, promotes RNA uptake, TLR8 activation and the release of cytokines, chemoattractants and neutrophil extracellular traps (NETs) by PMN, thus enhancing disease pathology. Whilst the skin microbiota regulate LL37 expression, LL37 in turn may shape RNA-modulated innate and adaptive immune responses by prompting RNA release from bacteria (by its antibacterial properties), complexation, and cellular uptake. Unfortunately, these interconnections and the physiological role of RNA sensing in skin immunity remain poorly understood. Our joint approach will combine microbiologist T. Eigenbrod’s expertise in microbial RNA sensing and in vivo infection models with the previous work of PI Weber on RNA/LL37-mediated responses in PMN in the psoriasis context. Together we will first determine the effects of both host and microbiota RNA recognition on key skin immune cell populations with relevance for psoriasis and skin infections. The effect of cell type (e.g. keratinocytes vs. classical skin immune cells) and bacterial strain will be especially studied in vitro and their relevance also explored in vivo (work area 1). Secondly, we will identify specific physiological sources and mechanisms of RNA-driven innate responses (e.g. NETosis) in the context of psoriasis. The origin of immunostimulatory RNA in the skin, effects of LL37 on its release, and the releasing microbiota will be in focus here (work area 2). Additionally, we will investigate the adjuvant properties of RNA and their influence on adaptive immunity. Specifically, we will study APC properties upon RNA exposure and determine changes in the presented MHC peptide ligandome in vitro and in skin samples (work area 3). Apart from the fundamental mechanisms, exploration of the therapeutic tractability of these processes by TLR-inhibitory oligodeoxynucleotides (iODNs) will also be advanced.