Investigation of the synovial tissue-homing mechanisms of circulating mononuclear phagocytes in treatment-naïve psoriatic arthritis.

Psoriatic arthritis (PsA) is a common immune-mediated chronic inflammatory arthritis (IA) with no existing biomarker and is associated with permanent joint damage and significant sequelae. A key feature is abnormal recruitment of leukocytes into joint tissues and increased vascularisation that facilitates this. The mechanisms underlying this infiltration are poorly understood. Mononuclear phagocytes (MPs) are abnormal in PsA, involved in neovascularisation, and the production/development of key cytokines and adaptive effectors. I aimed to identify the key interactions that drive MPs migration to joint tissue in active treatment-naïve PsA. I profiled each circulating MPs subset from health and active treatment naïve PsA patients by bulk RNA sequencing. This identified the differences in tissue homing and adhesion markers between the different MPs subsets. I used this to create a suspension mass cytometry panel to further explore 25-different tissue homing markers on blood MPs from healthy, PsA, and cutaneous psoriasis without arthritis (PsC) donors. I discovered a subset of cMos enriched for dendritic cell specific transmembrane protein (DCSTAMP), a marker of osteoclastogenesis, and multiple synovial tissue homing markers. These cells are expanded in PsA compared to healthy and PsC donors. Through transcriptomic and functional analysis, I show that these cells are bona fide pre-osteoclasts (preOC), bearing a similar transcriptomic signature to monocyte-osteoclast intermediaries generated in vitro. They form multinucleated osteoclasts without exogenous receptor activator of nuclear factor-κβ ligand (RANKL), and produce pro-inflammatory cytokines. Finally, I find that preOC home to psoriatic synovial tissues. Using synovial scRNAseq, I show enrichment of the same tissue homing signature on synovial osteoclast-like cells, and expression of the cognate ligands on PsA endothelium. Using technetium-99m (Tc99m) monocyte radiolabelling studies, I show recruitment of monocytes to inflamed PsA joints. Spatial sequencing and imaging mass cytometry of biopsies from these patients show several foci of Tc99 positive cells in PsA synovium, all of which align with the phenotype of preOC. Given the small number of monocytes estimated to enter synovial tissue, this further supports our hypothesis that preOC preferentially home to joint tissues in comparison to normal monocytes. Together, this work provides a new framework for exploring the governance of tissue homing of immune cells in humans, and a way to timestamp/lineage-trace blood origin cells into human tissues, and deeply phenotype them.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Hutton, Joe

Advisors dc:contributor.advisor

• McGovern, Naomi
• Summers, Charlotte

• myeloid
• macrophage
• dendritic cell
• psoriatic arthritis
• tissue homing
• trafficking
• osteoclast

Licence

• https://www.repository.cam.ac.uk/bitstreams/d963577e-2b62-4798-a9c4-5e98f9408732/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

Author Identifier

0000-0003-3013-2429

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/394080