TR156 C10 - Platelets as novel contributors to psoriasis skin autoinflammation

01/07/2023 to 30/06/2027

Psoriasis is an inflammatory autoimmune disease characterized by skin lesions with massive infiltration of immune cells and is frequently also associated with cardiovascular co-morbidities. Especially polymorphonuclear neutrophils (PMNs) drive psoriatic skin inflammation but how they home to the skin and are modulated in their activity remains unclear. In an unbiased screen of 332 surface antigens on primary human blood PMNs, the Weber lab identified platelet surface antigens as a defining feature of psoriasis PMNs due to a significantly increased formation of platelet-neutrophil complexes (PNCs) in psoriasis patients. Surprisingly, in psoriatic but not in healthy skin, platelets were detected in direct contact with PMNs. Similarly, in the topical imiquimod (IMQ)-induced mouse model of psoriasis, disease induction promoted PNC formation and platelet skin homing. Importantly, in vivo depletion of circulating platelets ameliorated skin disease severity significantly and completely abrogated PMN skin homing and neutrophil extracellular trap (NET) release. Thus, platelets appear to be novel contributors to psoriasis pathology and disease severity. As the mechanism and dynamics of platelet skin homing are unknown, we will firstly address how, mechanistically, platelets infiltrate into the psoriatic skin in the localized IMQ-induced skin inflammation. Secondly, we will explore which of the pleiotropic functions described for platelets (degranulation, cytokine release, migration, sensitization of PMN) apply to platelets found in psoriasis skin lesions and how their activity affects keratinocytes, dermal fibroblasts and infiltrating immune cells other than PMN. As a comparison to the localized IMQ-induced model, we will use a chronic genetic mouse model of psoriasis-like skin disease (K14-IL-17Aind/+) that allows to also study the skin-specific role of platelets in animals displaying systemic vascular inflammation. Our study will use low-invasive longitudinal and multiphoton intravital microscopy as a key technology established in the Weigelin lab. Monitoring live platelets, PMN and monocytes in both, topical and systemic psoriasis models, will provide deep dynamic insights which are combined with in vitro approaches for studying human and murine platelet-keratinocyte co-cultures and biopsies. Thereby, we aim to comprehensively describe the newly discovered role of platelets in psoriasis and shed light onto the fundamental principles of platelet skin-specific functions. Ultimately, our study may contribute to novel topical or systemic platelet-directed interventions to address both skin inflammation and cardiovascular risk in psoriasis patients.