A senescent iCAF-like fibroblast state governs therapy resistance in rheumatoid arthritis
Yoshihara, R.; Nakajima, S.; Yamazato, R.; Yoshida, T.; Takazawa, I.; Omata, Y.; Wang, T.-W.; Ishigaki, K.; Itamiya, T.; Ota, M.; Yasunaga, Y.; Fujieda, Y.; Matsumoto, T.; Shoda, H.; Yamamoto, K.; Tamura, N.; Mimura, T.; Ohmura, K.; Morinobu, A.; Atsumi, T.; Tanaka, Y.; Takeuchi, T.; Suzuki, Y.; Nakanishi, M.; Okamura, T.; Tanaka, S.; Tsuchiya, H.; Fujio, K.
Show abstract
Fibroblasts play a dual role in shaping tissue homeostasis and immune responses during inflammatory perturbations. Manipulating fibroblast behavior has therefore emerged as a promising strategy for autoimmune diseases. Here, through integrated multimodal single-cell transcriptomic and proteomic profiling of synovial tissue combined with prospective clinical data from 54 patients with rheumatoid arthritis, we identify C-X-C motif chemokine 12 (CXCL12)hi Apolipoprotein C1 (APOC1)+ fibroblasts as a pathogenic cell population driving refractory synovitis. CXCL12hi APOC1+ fibroblasts construct local niche in spatial coordinates with plasmablasts via the CXCL12-CXCR4 axis. APOC1 orchestrates senescent inflammatory cancer-associated fibroblast(iCAF)-like properties of this cluster through activation of the STAT3-C/EBP pathway. Therapeutic elimination of senescent cells, either alone or in combination with TNF inhibition, significantly ameliorates experimental arthritis. Together, these findings uncover a mechanistic basis for treatment resistance in rheumatoid arthritis and highlight senescent iCAF-like fibroblasts as a promising therapeutic target.
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