Fibroblast-like synoviocytes mediate the generation of soluble PD-1 in an MMP-9-dependent manner: a novel target therapy for rheumatoid arthritis.

INTRODUCTION: Dysregulated T cell homeostasis leading to enhanced immune responses is a critical pathogenic mechanism in rheumatoid arthritis (RA). Programmed cell death protein 1 (PD-1) is a crucial immune checkpoint that modulates T cell activity. Soluble PD-1 (sPD-1) may contribute to the sustained activation of T cells. Investigating the mechanisms of sPD-1 production and its role in RA pathogenesis is essential for the development of alternative treatment strategies. METHODS: A total of 122 patients with RA and 68 Health controls were enrolled in this study. We assessed PD-1 expression in T cells from patients with RA and measured sPD-1 levels in plasma, revealing a correlation between sPD-1 and disease activity progression in patients with RA. Furthermore, we examined the potential mechanisms underlying sPD-1 production in RA patients. Additionally, we evaluated the therapeutic effects of PD-L1-MSA, a fusion protein containing C-terminal PD-L1 and full-length MSA, in collagen-induced arthritis (CIA) mice. RESULTS: Clinical analyses indicated that plasma sPD-1 levels positively correlated with indicators of disease activity. The generation of sPD-1 primarily resulted from matrix metalloproteinase-9 (MMP-9)-mediated shedding of surface PD-1 from activated T cells, with MMP-9 being derived from fibroblast-like synoviocytes (FLS). Additionally, therapeutic evaluation in collagen-induced arthritis (CIA) mice demonstrated that PD-L1-MSA, a fusion protein containing C-terminal PD-L1 and full-length mouse serum albumin (MSA), significantly mitigated pathological changes. DISCUSSION: These results indicate that plasma sPD-1 levels are positively associated with RA disease activity, supporting its potential as a complementary biomarker for monitoring disease activity (especially in combination with traditional indicators like CRP/ESR), though its standalone diagnostic value requires further validation. Furthermore, targeting sPD-1, such as with PD-L1-MSA, represents a promising complementary therapeutic candidate for alleviating RA pathology.