706 Single cell transcriptomic analysis of the peripheral neutrophil compartment in psoriatic arthritis reveals heterogeneity and novel potential therapeutic targets

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory disease that affects approximately 20% of patients with plaque psoriasis (PsO). Neutrophil subsets are elevated in psoriatic disease, however their role in chronic inflammation and mechanisms driving synovio-entheseal inflammation has yet to be fully elucidated. We performed single cell RNASeq of peripheral blood neutrophils from age- and sex-matched patients to identify neutrophil specific pathways driving the development of PsA. Machine learning was performed for non-linear dimension reduction analysis and revealed significant heterogeneity within the neutrophil compartment, identified specific clusters enriched in PsA patients, and key molecular genes and networks (extracellular matrix remodeling, adhesome and inflammasome) that are differentially regulated in neutrophils from patients suffering psoriatic arthritis vs. plaque psoriasis. We also generated complex pseudotime trajectories to accurately reconstruct neutrophil biological transition states. We identified key regulatory genes and transcription factors such as MEF2C, shown to promote myeloid progenitor proliferation in a mouse model, and whose deletion suppresses progenitor expansion and corrects neutrophilia in miR-223-/- mice. We identified novel potential therapeutic targets for preventing or reversing neutrophil-mediated mechanisms driving psoriatic arthritis, and significantly expanded our understanding of the complicated disease pathophysiology that differentiates psoriatic arthritis from plaque psoriasis to guide therapeutic approaches.