SFB/TRR156/1

Teilprojekt B05: TLR signaling in Neutrophilen als möglicher Therapieansatz in Psoriasis

01.07.2015 bis 30.06.2019

Psoriasis is a chronic inflammatory disease with high incidence in Western countries and substantial morbidity, but limited therapeutic approaches. Psoriatic lesions are characterized by an infiltration of polymorphonuclear leukocytes (PMNs) and T cells, paralleled by an accumulation of the peptide LL-37. LL-37 was proposed to act as a PMN chemo-attractant and to complex nucleic acids, thereby promoting innate immune stimulation via nucleic acid-sensing receptors, such as Toll-like receptors (TLRs) TLR8 or TLR9. Multiple lines of evidence suggest that PMNs are key players in the inflammatory micro-milieu found in psoriatic skin: Firstly, PMNs are the main source of LL-37. Secondly, human PMN express TLR8 and TLR9 and, by a process termed NETosis, provide extracellular nucleic acids that may fuel a self-amplifying vicious cycle of PMN activation via LL-37-nucleic acid complexes. Preliminary data from our lab shows that TLR8 activation in PMNs promotes LL-37 release. We further could show that TLR8 activation in PMN drives pro-inflammatory cytokine expression, which is a hallmark of psoriasis. Further studies from our group show that a T-cell suppressive PMN subtype is reduced in psoriasis patients. Unfortunately, much of what is known about PMN has been derived from studies in blood PMN. Given the pivotal, but poorly defined role of skin-homed PMN in psoriasis, we see a strong rationale for dissecting the role of PMN in the skin context, focusing particularly on TLR-LL-37 mediated control circuits, contribution to the inflammatory milieu, and the balance between effector and suppressor PMN. Differences between mice and humans regarding TLR expression/functionality as well as the relevance of PMNs in the murine vs. human immune system highlight the need for such studies in the human system. A particular focus of the project that we can ideally address within this CRC will also be to dissect the so far enigmatic interplay of PMN with T cells, keratinocytes, slanDC and innate lymphoid cells, all of which have a role to play in psoriasis. Building on our expertise in TLRs and PMNs and strong links with dermatologists within the CRC, our studies will involve in vitro and ex vivo analysis of psoriasis-relevant cell types from biopsy material and skin sections from psoriatic and non-psoriatic patients, complemented by follow-up experiments in the murine model of psoriasis. Using this rigorous methodology we hope to provide a much clearer definition for the role of PMNs in psoriasis and at the same time provide novel points of intervention in the management or cure of psoriasis.