Third Party Funds Group - Sub project
Acronym: SFB 1526 / PANTAU TP B04
Start date : 01.01.2022
End date : 30.06.2026
Website: https://www.sfb1526.uni-luebeck.de
In pemphigoid diseases (PDs), neutrophils are central effector cells of autoantibody-induced tissue pathology. In response to activation of their Fcγ receptors (FcγRs) by pathogenic IgG autoantibodies deposited at the dermal-epidermal junction (DEJ), they unleash their effector mechanisms. This includes the release of proteases and reactive oxygen species (ROS) resulting in degradation of the dermal-epidermal adhesion complex, which ultimately leads to the formation of skin blisters and erosions. The signal transduction pathways activated downstream of FcγRs are considered to mainly consist of consecutive activation of kinases. These kinase cascades trigger effector mechanisms and are hence potential therapeutic targets. However, the cascades downstream of FcγRs are still only partially understood, which complicates the development of therapeutic strategies specifically targeting those kinases involved in triggering neutrophil effector functions in response to FcγR activation. The research program proposed here therefore aims to comprehensively characterize the kinase cascades downstream of FcγR activation and to examine the effect of inhibiting select kinases for therapeutic purposes in PDs.
In preliminary studies, we have recently characterized FcγR signaling by two synergizing approaches: (i) by an unbiased profiling of kinase activity in neutrophils after immune complex (IC) activation and (ii) by screening of a chemical library of 141 target-selective inhibitors of signal transduction enzymes, including many kinases, for their effect on IC-induced ROS release from neutrophils. Thus, we have highlighted several kinases, previously not implicated in FcγR signaling, to be activated in response to ICs and established an essential role in eliciting neutrophil effector mechanisms in vitro for some of these kinases. By use of selective pharmacological inhibitors, we will now characterize the role of key kinases in IC-mediated neutrophil activation. We will also determine the therapeutic potential of select kinase inhibitors in vivo in established mouse models of PD. In parallel, to corroborate the relevance of our findings for the human situation, we will profile the kinome of unstimulated and IC-stimulated neutrophils and of lesional skin from PD patients. Finally, to further drive clinical translation, particularly of therapeutic approaches targeting cell signaling transduction in neutrophils and other myeloid cells in PDs, we will establish a novel mouse model for PDs featuring a humanized immune system. We will employ this model to examine the therapeutic potential of select kinase inhibitors in PDs.