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

Chao Yang^1,2Miao Ma³Kangjie Yu⁴Yi Wang²Yuting Zhang⁵Yan Shen²Jun Wang²Xiaoke Wang^1,2Lulu Luo^1,2Ya Zhao^2*

• ¹College of life sciences, Northwest University, Xi'an, China
• ²College of Basic Medical Sciences, Department of Medical Microbiology and Parasitology, Air Force Medical University, Xi'an, China
• ³Department of rheumatology and immunology, Air Force Medical University Tangdu Hospital, Xi'an, China
• ⁴Department of Pathology, Air Force Hospital of Eastern Theater Command, Nanjing, China
• ⁵Xijing Hospital, Department of Nephrology, Air Force Medical University, Xi'an, China

T cell homeostasis dysregulation, which drives enhanced immune responses, is a critical pathogenic mechanism in rheumatoid arthritis (RA). Soluble programmed cell death protein 1 (sPD-1) may contribute to this process by sustaining T cell activation. In this study, we assessed the role of sPD-1 in RA by enrolling 122 patients and 68 healthy controls, finding that plasma sPD-1 levels positively correlated with indicators of disease activity. We further investigated the mechanisms underlying sPD-1 production, revealing that its generation primarily results 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. 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 to alleviate RA pathology.