TR156 B05 - Immaktivierung durch mikrobielle und Wirts-RNA in der Haut

01.07.2023 bis 30.06.2027

RNA sensing within skin innate immunity contributes to defense of infectious organisms but also plays
a role in autoimmunity. The Weber group showed that LL37 converts both host and bacterial RNA into
a trigger for TLR8 in neutrophils (PMN) resulting in formation of neutrophil extracellular traps (NETs).
They discovered NET-associated RNA (naRNA) which further propagates inflammation and plays a role
in psoriasis. The Dalpke group now joins the project and has a longstanding expertise in bacterial RNA
recognition. They showed that TLR/RNA recognition is critical for limiting skin infections with
Streptococcus pyogenes, and that RNA modifications affect RNA recognition. As TLR8 requires RNA
processing and as RNase 7 is a highly abundant antimicrobial peptide (AMP) in the skin, we hypothesize
that RNase 7 may act in concert with LL37 in regulating skin RNA responses. We will now further explore
the role of naRNA in psoriasis skin pathology and inflammation, and the role of skin RNases in this selfamplifying inflammatory process (work area 1). Furthermore, we will extend analyses to link naRNA and
anti-RNA auto-antibodies in systemic lupus and psoriasis (work area 2). Moreover, skin-relevant RNase
7, LL37 and TLR8 signaling will be studied in host RNA versus commensal microbial RNA sensing in
keratinocytes, PMN and human skin models (work area 3). Finally, disease-related microbiota
differences, type and abundance of RNA modifications in skin microbes, and their RNA/TLR8 stimulatory
potential will be determined for healthy vs psoriasis skin (work area 4). Based on previous work
identifying inhibitory RNA modifications we will also use inhibitory oligo-ribonucleotides to explore their
use in limiting inflammatory reactions to bacteria and NETs in the context of skin inflammation.