Kurzfassung

The activation of innate immune cells is mainly regulated by surface receptors, either recognizing inflammatory mediators (such as TNF-α, IL-1β, IL-6, IL-10 etc.), or pathogen associated molecular patterns (PAMPs) directly, e.g. via toll-like receptors (TLR), NACHT-LRR receptors (NLR) or C-type lectins. In this context, the triggering receptor expressed on myeloid cells (TREM)-1 has been described in mice and humans as an activating receptor of the immunoglobulin (Ig) superfamily expressed on...The activation of innate immune cells is mainly regulated by surface receptors, either recognizing inflammatory mediators (such as TNF-α, IL-1β, IL-6, IL-10 etc.), or pathogen associated molecular patterns (PAMPs) directly, e.g. via toll-like receptors (TLR), NACHT-LRR receptors (NLR) or C-type lectins. In this context, the triggering receptor expressed on myeloid cells (TREM)-1 has been described in mice and humans as an activating receptor of the immunoglobulin (Ig) superfamily expressed on polymorphonuclear neutrophils (PMN), as well as on monocytes and macrophage subpopulations 1 modulating TLR or NLR mediated cell activation 2. TREM-1 associates with the adapter protein DAP12 for signal transduction resulting in the release of pro-inflammatory chemokines and cytokines, increased surface expression of cell activation markers and degranulation 3. In this context, we have recently demonstrated that TREM-1 specific neutrophil activation is strictly Bruton tyrosine kinase (BTK) dependent and can be inhibited by the specific inhibitor ibrutinib in vitro as well as in vivo in mice and humans suggesting that TREM-1 dependent immune responses can be targeted by this inhibitor 4.
TREM-1 up-regulation on neutrophils and monocytes has been initially detected in vitro after activation with bacteria, such as Pseudomonas aeruginosa and Staphylococcus aureus, and has been confirmed by immunohistochemistry in vivo. High expression levels of TREM-1 have been detected in inflammatory skin lesions caused by bacteria and fungi, e.g. in folliculitis and impetigo, but not as pronounced in lesions caused by non-infectious inflammatory processes, such as in vasculitis and psoriasis 5. Nevertheless, elevated TREM-1 expression in dendritic cells within psoriatic lesions as well as increased levels of soluble TREM-1 have been recently described in psoriasis patients 6. This was associated with disease severity and response to psoriasis treatment (IL-17A or TNF-α blocking antibodies), suggesting TREM-1 as a novel target in psoriasis.
Taken together, there seems to be a significant contribution of TREM-1 in the regulation of inflammatory processes in the skin. Nevertheless, there are currently many open questions to be answered in order to acknowledge the true function of TREM-1. Besides the still elusive TREM-1 ligands, it is currently unclear how TREM-1 contributes to these apparently discrepant results described above. In our project proposal, we will address the cell-specific contribution of TREM-1 under steady state conditions as well as in a murine S. aureus skin infection model and in a psoriasis-like mouse model, allowing us to conclude on specific functions of TREM-1 under these inflammatory conditions. This will open novel perspectives to modulate TREM-1 activity using inhibitors specific for TREM-1 such as receptor-blocking peptides LP17 and GF9 or the BTK inhibitor ibrutinib .
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